Randomized controlled phase III trial to investigate superiority of robot-assisted gastrectomy over laparoscopic gastrectomy for clinical stage T1-4aN0-3 gastric cancer patients (JCOG1907, MONA LISA study): a study protocol.

BACKGROUND: Laparoscopic gastrectomy (LG) is considered a standard treatment for clinical stage I gastric cancer. Nevertheless, LG has some drawbacks, such as motion restriction and difficulties in spatial perception. Robot-assisted gastrectomy (RG) overcomes these drawbacks by using articulated forceps, tremor-filtering capability, and high-resolution three-dimensional imaging, and it is expected to enable more precise and safer procedures than LG for gastric cancer. However, robust evidence based on a large-scale randomized study is lacking. METHODS: We are performing a randomized controlled phase III study to investigate the superiority of RG over LG for clinical T1-2N0-2 gastric cancer in terms of safety. In total, 1,040 patients are planned to be enrolled from 46 Japanese institutions over 5 years. The primary endpoint is the incidence of postoperative intra-abdominal infectious complications, including anastomotic leakage, pancreatic fistula, and intra-abdominal abscess of Clavien-Dindo (CD) grade ≥ II. The secondary endpoints are the incidence of all CD grade ≥ II and ≥ IIIA postoperative complications, the incidence of CD grade ≥ IIIA postoperative intra-abdominal infectious complications, relapse-free survival, overall survival, the proportion of RG completion, the proportion of LG completion, the proportion of conversion to open surgery, the proportion of operation-related death, and short-term surgical outcomes. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in January 2020. Approval from the institutional review board was obtained before starting patient enrollment in each institution. Patient enrollment began in March 2020. We revised the protocol to expand the eligibility criteria to T1-4aN0-3 in July 2022 based on the results of randomized trials of LG demonstrating non-inferiority of LG to open surgery for survival outcomes in advanced gastric cancer. DISCUSSION: This is the first multicenter randomized controlled trial to confirm the superiority of RG over LG in terms of safety. This study will demonstrate whether RG is superior for gastric cancer. TRIAL REGISTRATION: The protocol of JCOG1907 was registered in the UMIN Clinical Trials Registry as UMIN000039825 ( http://www.umin.ac.jp/ctr/index.htm ). Date of Registration: March 16, 2020. Date of First Participant Enrollment: April 1, 2020.

Patient-reported outcome and quality of life research policy: Japan Clinical Oncology Group (JCOG) policy.

Assessments of patient-reported outcomes and health-related quality of life in cancer clinical trials have been increasingly emphasized recently because patient and public involvement in cancer treatment development has been promoted by regulatory authorities and academic societies. To assess patient experiences during and after cancer treatment, there is interest in implementing patient-reported outcome and health-related quality of life assessments into cancer clinical trials. The Japan Clinical Oncology Group quality of life ad hoc committee previously created a version of the Quality of Life Assessment Policy in 2006. Recently, there has been increasing demand from Japan Clinical Oncology Group researchers to assess patient-reported outcome/health-related quality of life in clinical trials. Although guidelines are available regarding planning and reporting clinical trials that include patient-reported outcome/health-related quality of life as an endpoint, there are still issues regarding the lack of consensus on standardized methods for analysing and interpreting the results. Hence, it was considered necessary to reorganize the Japan Clinical Oncology Group patient-reported outcome/quality of life research committee and to revise the former patient-reported outcome/quality of life research policy to promote patient-reported outcome/health-related quality of life research in future Japan Clinical Oncology Group trials. The purpose of this Japan Clinical Oncology Group patient-reported outcome/quality of life research policy is to define patient-reported outcome/health-related quality of life research and provide guidelines for including patient-reported outcome/health-related quality of life as an endpoint in Japan Clinical Oncology Group trials.

A new era of the Asian clinical research network: a report from the ATLAS international symposium.

This report summarizes the presentations and discussions in the first Asian Clinical Trials Network for Cancers (ATLAS) international symposium that was held on 24 April 2022, in Bangkok, Thailand, and hosted by the National Cancer Center Hospital (NCCH), co-hosted by the Pharmaceuticals and Medical Devices Agency (PMDA), Clinical Research Malaysia (CRM) and the Thai Society of Clinical Oncology (TSCO), and supported by Embassy of Japan in Thailand. Since 2020, the NCCH has conducted the ATLAS project to enhance research environments and infrastructures to facilitate international clinical research and cancer genomic medicine in the Asian region. The purpose of the symposium was to discuss what we can achieve under the ATLAS project, to share the latest topics and common issues in cancer research and to facilitate mutual understanding. Invitees included stakeholders from academic institutions, mainly at ATLAS collaborative sites, as well as Asian regulatory authorities. The invited speakers discussed ongoing collaborative research, regulatory perspectives to improve new drug access in Asia, the status of phase I trials in Asia, the introduction of research activities at the National Cancer Center (NCC) and the implementation of genomic medicine. As the next steps after this symposium, the ATLAS project will foster increased cooperation between investigators, regulatory authorities and other stakeholders relevant to cancer research, and establish a sustainable pan-Asian cancer research group to increase the number of clinical trials and deliver novel drugs to patients with cancer in Asia.

Systematic review of health-related quality of life (HRQoL) issues associated with gastric cancer: capturing cross-cultural differences.

The treatment landscape for gastric cancer (GC) is constantly evolving with therapies affecting all aspects of health-related quality of life (HRQoL) which need careful monitoring. While there are HRQoL measures designed specifically to capture issues relevant to patients with GC, these might be outdated and only relevant to patients in westernised cultures. This review identifies the patient-reported measures used to assess HRQoL of patients with GC and compares the HRQoL measures used across cultures including East Asia, where GC is more prevalent. We conducted a systematic review of publications between January 2001 and January 2021. A total of 267 papers were identified; the majority (66%) of studies involved patients from East Asian countries. Out of the 24 HRQoL questionnaires captured, the European Organisation for Research and Treatment of Cancer Core Cancer measure (QLQ-C30) was the most widely used (60% of all studies and 62% of those involving patients from East Asian countries), followed by its gastric cancer-specific module (QLQ-STO22, 34% of all studies and 41% from East Asia). Eight questionnaires were developed within East Asian countries and, of the 20 studies including bespoke questions, 16 were from East Asia. There were six qualitative studies. HRQoL issues captured include diarrhoea, constipation, reflux, abdominal pain and abdominal fulness or bloating, difficulty swallowing, restricted eating, and weight loss. Psychosocial issues related to these problems were also assessed. Issues relating to the compatibility of some of the westernised measures within East Asian cultures were highlighted.

Results from a 1-day workshop on the assessment of quality of life in cancer patients: a joint initiative of the Japan Clinical Oncology Group and the European Organisation for Research and Treatment of Cancer.

This report summarizes the presentations and discussion in the first Japan Clinical Oncology Group-European Organisation for Research and Treatment of Cancer Quality of Life/Patient-Reported Outcome workshop funded by the National Cancer Center Hospital that was held on Saturday, 1 September 2018 in Tokyo, Japan. The infrastructure and understanding regarding the Quality of Life/Patient-Reported Outcome assessment of cancer patients in Japan is still immature, in spite of the increased demand for oncological Patient-Reported Outcome research felt not only by researchers but also by patients or other stakeholders of cancer drug development. The workshop aimed to share each perspective, common issues to be considered and future perspectives regarding the strong alliance between the European Organisation for Research and Treatment of Cancer Quality of Life Group and the Japan Clinical Oncology Group for Quality of Life/Patient-Reported Outcome research as well as explore the possibility of conducting collaborative research. European Organisation for Research and Treatment of Cancer is a leading international cancer clinical trials organization, and its Quality of Life Group is a global leader in the implementation of Quality of Life research in cancer patients. The three invited speakers from the European Organisation for Research and Treatment of Cancer Quality of Life Group presented their perspective, latest methodology and ongoing projects. The three speakers from the Japan Clinical Oncology Group presented their current status, experience and some issues regarding data management or interpretation of the Patient-Reported Outcome data. The two patient advocates also shared their expectations in terms of advances in cancer research based on the Patient-Reported Outcome assessment. As the next steps after this workshop, the Japan Clinical Oncology Group and European Organisation for Research and Treatment of Cancer have decided to cooperate more closely to facilitate Patient-Reported Outcome research in both the groups, and the Japan Clinical Oncology Group has approved the establishment of a new committee for Quality of Life/Patient-Reported Outcome research in Japan.

Responding to the challenges of international collaborations between the east and the west - report of the first JCOG-EORTC symposium and a perspective from young JCOG and EORTC investigators.

International/intercontinental collaboration is necessary to set up new innovative clinical trials for cancer treatment. However, the infrastructure, especially Asia-Europe academic partnerships, to enable such collaboration has not been fully structured and differences and similarities between the research groups have not been well studied. In 2015, collaboration started between the biggest cancer research organizations in Asia and EU, Japan Clinical Oncology Group (JCOG) and European Organisation for Research and Treatment of Cancer (EORTC). Following the first pilot collaboration study, the first scientific symposium took place in December 2017 in Tokyo. Before the symposium, a working visit for EORTC investigators from the Early Career Investigator initiative (ECI), willing to develop projects within the JCOG-EORTC partnership, was held. In addition to the digest of the working visit and symposium, we aimed to describe the differences and similarities between the two groups and to identify key factors for collaboration from the perspective of the young investigators of the networks. These findings are described in this article.

Phase III study of tri-modality combination therapy with induction docetaxel plus cisplatin and 5-fluorouracil versus definitive chemoradiotherapy for locally advanced unresectable squamous-cell carcinoma of the thoracic esophagus (JCOG1510: TRIANgLE).

A randomized phase III trial commenced in Japan in February 2018. Definitive chemoradiotherapy (CRT) with cisplatin plus 5-fluorouracil is the current standard treatment for locally advanced unresectable esophageal carcinoma. The purpose of this study is to confirm the superiority of induction chemotherapy with docetaxel plus cisplatin and 5-fluorouracil (DCF) followed by conversion surgery or definitive CRT over definitive CRT alone for overall survival (OS) in patients with locally advanced unresectable squamous-cell carcinoma of thoracic esophagus. A total of 230 patients will be accrued from 47 Japanese institutions over 4.5 years. The primary endpoint is OS, and the secondary endpoints are progression-free survival, complete response rate of CRT, response rate of DCF, adverse events of DCF and CRT, late adverse events and surgical complications. This trial has been registered at the Japan Registry of Clinical Trials as jRCTs031180181.

Evaluation of the prognostic factors in patients with pT3N0 or pT1N2-3 gastric cancer: a single institutional retrospective cohort study.

PURPOSE: The impact of adjuvant chemotherapy on the survival of patients with the pT3N0/pT1N2-3 subset of Stage II gastric cancer is unclear. The aim of this study was to evaluate the survival rate of pT3N0/pT1N2-3 patients who were treated by surgery alone and to identify a high-risk group within this cohort. METHODS: A total of 258 patients with pT3N0/pT1N2-3 gastric cancer who underwent gastrectomy alone in our hospital between January 1992 and December 2012 were enrolled in the present study. Their medical records were retrospectively reviewed to evaluate the survival rates and investigate prognostic factors. RESULTS: The 3- and 5-year recurrence-free survival rates of this cohort were 84 and 80%, respectively. The 3- and 5-year overall survival rates were 89 and 83%, respectively. A multivariate analysis revealed that pathological venous infiltration was an independent prognostic factor. The survival of patients with pathological venous infiltration was significantly worse than that of those without (5-year recurrence-free survival, 75 vs. 90%, p = 0.0005; 5-year overall survival, 78 vs. 91%, p = 0.0062). CONCLUSIONS: The prognosis of pT3N0/pT1N2-3 gastric cancer patients treated by surgery alone was relatively good; however, patients with pathological vessel infiltration may be at high risk of recurrence and could be candidates for adjuvant chemotherapy.

Long-term Outcomes of Laparoscopic Versus Open Surgery for Clinical Stage I Gastric Cancer: The LOC-1 Study.

BACKGROUND: Clinical trials comparing laparoscopic gastrectomy (LG) versus traditional open gastrectomy (OG) have been planned, their surgical outcomes reported but their oncologic outcomes are still pending. Consequently, we have conducted this large-scale historical cohort study to provide relevant information rapidly to guide our current practice. METHODS: Through a consensus meeting involving surgeons, biostatisticians, and epidemiologists, 30 variables of preoperative information possibly influencing surgeons' choice between LG versus OG and potentially associating with outcomes were identified to enable rigorous estimation of propensity scores. A total of 4235 consecutive patients who underwent gastrectomy for gastric adenocarcinoma were identified and their relevant data were gathered from the participating hospitals. After propensity score matching, 1848 patients (924 each for LG and OG) were selected for comparison of long-term outcomes. RESULTS: In the propensity-matched population, the 5-year overall survival was 96.3% [95% confidence interval (CI) 95.0-97.6] in the OG as compared with 97.1% (95% CI, 95.9-98.3) in LG. The number of all-cause death was 33/924 in the OG and 24/924 in the LG through the entire period, and the hazard ratio (LG/OG) for overall death was 0.75 (95% CI, 0.44-1.27; P = 0.290). The 3-year recurrence-free survival was 97.4% (95% CI, 96.4-98.5) in the OG and 97.7% (95% CI, 96.5-98.8) in the LG. The number of recurrence was 22/924 in the OG and 21/924 in the LG through the entire period, and the hazard ratio was 1.01 (95% CI, 0.55-1.84; P = 0.981). CONCLUSIONS: This observational study adjusted for all-known confounding factors seems to provide strong enough evidence to suggest that LG is oncologically comparable to OG for gastric cancer.

Statistical Analysis Methods and Reporting of Patient-Reported Outcomes in Randomized Controlled Trials for Cancer Conducted in Japan: A Systematic Review.

The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative was established in 2016 to assess the quality and standardization of patient-reported outcomes (PRO) data analysis in randomized controlled trials (RCTs) on advanced breast cancer. The initiative identified deficiencies in PRO data reporting, including nonstandardized methods for handling missing data. This study evaluated the reporting of health-related quality of life (HRQOL) in Japanese cancer RCTs to provide insights into the state of PRO reporting in Japan. The study reviewed PubMed articles published from 2010 to 2018. Eligible studies included Japanese cancer RCTs with ≥50 adult patients (≥50% were Japanese) with solid tumors receiving anticancer treatments. The evaluation criteria included clarity of the HRQOL hypotheses, multiplicity testing, primary analysis methods, and reporting of clinically meaningful differences. Twenty-seven HRQOL trials were identified. Only 15% provided a clear HRQOL hypothesis, and 63% examined multiple HRQOL domains without adjusting for multiplicity. Model-based methods were the most common statistical methods for the primary HRQOL analysis. Only 22% of the trials explicitly reported clinically meaningful differences in HRQOL. Baseline assessments were reported in most trials, but only 26% reported comparisons between the treatment groups. HRQOL analysis was based on the intention-to-treat population in 19% of the trials, and 74% reported compliance at follow-up; however, 41% did not specify how missing values were handled. Although the rates of reporting clinical hypotheses and clinically meaningful differences were relatively low, the current state of HRQOL evaluation in the Japanese cancer RCT appears comparable to that of previous studies.

Clinical research in cancer palliative care: a metaresearch analysis.

OBJECTIVE: This metaresearch of the clinicaltrials.gov database aims to evaluate how clinical research on palliative care is conducted within the setting of advanced cancer. METHODS: Clinicaltrials.gov was searched to identify registered studies recruiting patients with cancer, and investigating issues relevant to palliative care. The European Organisation for Research and Treatment of Cancer QLQ-C15-PAL (Quality of Life in palliative cancer care patients) questionnaire was taken into account to define the research domains of interest. Studies investigating cancer-directed therapy, management of cancer treatment-related adverse events and diagnostic tests were excluded. Publication status was crosschecked using PubMed. RESULTS: Of 3950 identified studies, 514 were included. The most frequent reason for exclusion was cancer-directed therapy (2491). In 2007-2012, 161 studies were registered versus 245 in 2013-2018. Included studies were interventional (84%) or observational (16%). Most studies were monocentric (60%), sponsored by academia (79%), and conducted in North America (57%) or Europe (25%). Seventy-nine per cent of studies evaluated a heterogeneous population (>1 tumour type). Interventional studies most frequently investigated systemic drugs (34%), behavioural interventions (29%) and procedures for pain (24%). Pain, quality of life and physical function were the most frequently studied research domains (188, 95 and 52 studies, respectively). The most applied primary outcome measures were efficacy/symptom control (61%), quality of life (14%) and feasibility (12%). Only 16% of the closed studies had published results in PubMed. CONCLUSIONS: Our study describes the heterogeneous landscape of studies conducted to address the issues of patients with advanced cancer in palliative care. Albeit the observed increase in the number of studies over the last decade, the generalisation of the results brought by the existing trials is limited due to methodological issues and lack of reporting. A greater effort is needed to improve clinical research that supports evidence-based palliative cancer care.

Multidisciplinary management of stage II-III gastric and gastro-oesophageal junction cancer.

The aim of this manuscript is to discuss the viewpoint of the European Organisation for Research and Treatment of Cancer (EORTC) Gastric Cancer Taskforce and Japan Clinical Oncology Group (JCOG) Gastric Cancer Study Group on the current challenges in the multidisciplinary management of stage II-III gastric and gastro-oesophageal junction (GEJ) cancer. We seek to outline how these challenges are addressed in current trials of both groups. Key elements of future trials of EORTC and JCOG in this indication are described, and a joint vision on how multidisciplinary research of gastric and GEJ cancer patients should be organised is outlined.

Access to Clinical Trials for Adolescents and Young Adults With Cancer: A Meta-Research Analysis.

BACKGROUND: The 18-year-old age limit for inclusion in clinical trials constitutes a hurdle for adolescents and young adults (AYAs) with cancer. We analyzed the impact of this age barrier on the access of AYAs to cancer trials and novel therapies. METHODS: ClinicalTrials.gov was searched to identify all the trials including patients with 10 malignancies relevant for AYAs (January 2007 to July 2018). The trials were categorized as pediatric (patients <18 y), adult (≥18 y), and transitional (including adult and pediatric patients). Transitional trials with a lower limit between 12 and 18 years and an upper limit younger than 40 years were considered AYA-specific. RESULTS: Of 2764 identified trials, 2176 were included: 79% adult, 19% transitional, 2% pediatric. Five trials were AYA-specific. The proportion of academic trials was higher for transitional (69%; 288 of 421) than for adult trials (48%; 832 of 1718) (P < .0001). The total number of new trials increased over the years (156 in 2007; 228 in 2017); however, the number of transitional trials remained stable. The availability of trials increased with age, with a major increase at age 18 years: at age 17 years, 20% (442 of 2176) of trials were potentially accessible vs 95% (2075 of 2176) at 18 years. For trials investigating targeted therapies, this increase was 460% (197 trials available at age 17 years; 901 at 18 years) and for immunotherapies, 1200% (55 at age 17 years; 658 at 18 years). CONCLUSIONS: AYAs have limited access to cancer trials and innovative therapies, with no improvement over the last decade. The 18-years-old age limit continues to be a major hurdle. Our findings are consistent with the internationally supported idea that age inclusion criteria in oncological trials should be changed.