Overview of the ethical guidelines for medical and biological research involving human subjects in Japan.

The new national guidelines for clinical research, the Ethical Guidelines for Medical and Biological Research Involving Human Subjects, were implemented in Japan in June 2021. The guidelines were developed by integrating two ethical guidelines: Ethical Guidelines for Medical and Health Research Involving Human Subjects and Ethical Guidelines for Human Genome/Gene Analysis Research. The Ethical Guidelines for Clinical Research were originally developed as three separate guidelines: Ethical Guidelines for Human Genome/Gene Analysis Research formulated in 2001, Ethical Guidelines for Epidemiological Research in 2002 and Ethical Guidelines for Clinical Research in 2003. They have undergone several amendments and integration in response to the government's policy changes, such as the protection of personal information, conflicts of interest and reliability of clinical research. The three major changes introduced in the New Integrated Guidelines in 2021 are centralized review, electromagnetic informed consent and research cooperating organization. These are expected to be used as tools to facilitate the conduct of research. This review discusses the regulations of academic clinical research in Japan, the history of ethical guidelines and the three major changes introduced in the New Integrated Guidelines.

Significance of the timing of ureteral ligation on prognosis during radical nephroureterectomy for upper urinary tract urothelial cancer.

OBJECTIVES: To investigate the impact on intravesical recurrence and prognosis according to the ureteral ligation timing during radical nephroureterectomy for upper urinary tract urothelial carcinoma. METHODS: We carried out a retrospective chart review of 664 patients with non-metastatic upper urinary tract urothelial carcinoma who underwent radical nephroureterectomy with ureteral ligation (supplementary analysis of JCOG1110A). We excluded patients with previous and/or synchronous bladder cancer, clinically node-positive disease, no ureteral ligation data, those without ureteral ligation and those with any missing data. We investigated the cumulative incidence of intravesical recurrence and cancer-specific mortality, and overall survival between patients with ureteral ligation before renovascular ligation (early ureteral ligation), or ureteral ligation after renovascular ligation (late ureteral ligation). RESULTS: Early and late ureteral ligation was carried out in 243 patients (36.6%) and 421 patients (63.4%), respectively. Intravesical recurrence occurred in 218 patients (32.8%) during follow up (median 3.9 years). No significant difference in the intravesical recurrence was found between early and late ureteral ligation groups. Meanwhile, survival in the early ureteral ligation group was significantly worse compared with the late ureteral ligation group. Multivariable analysis showed that early ureteral ligation was an independent prognostic factor for overall survival (hazard ratio 1.88, 95% confidence interval 1.24-2.85, P = 0.003) and cancer-specific mortality (hazard ratio 1.93, 95% confidence interval 1.14-3.25, P = 0.014). CONCLUSIONS: Our findings suggest that the incidence of intravesical recurrence is not affected by the timing of ureteral ligation during radical nephroureterectomy. However, early ureteral ligation might have a negative impact on survival outcomes.

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.

[Conducting specified clinical trials under the Japanese clinical trials act].

Two years have passed since the Clinical Trials Act came into effect in April 2018. There were a series of research misconducts behind the legislation, and the Clinical Trials Act was enacted to ensure confidence in clinical trials conducted in Japan. The term "specified clinical trials" refers to clinical trials conducted using pharmaceuticals or medical devices, approval for which has not been obtained, or clinical trials conducted receiving research funds or other benefits provided by a manufacturer with marketing approval for pharmaceuticals or medical devices. The key elements in conducting specified clinical trials are as follows: (1) compliance with clinical trial standards, (2) approval by the certified review board, (3) submission of the trial plan to the Minister of Health, Labour, and Welfare, and (4) entering into an agreement with a manufacturer providing research funds. This manuscript overviews the Clinical Trials Act and the conduct of specified clinical trials by reviewing the key issues behind the legislation.

Impact of Previous, Simultaneous or Subsequent Bladder Cancer on Prognosis after Radical Nephroureterectomy for Upper Urinary Tract Urothelial Carcinoma.

PURPOSE: We investigated the impact of previous, simultaneous or subsequent bladder cancer on the clinical outcomes of upper urinary tract urothelial carcinoma. MATERIALS AND METHODS: We retrospectively collected data on 2,668 patients who underwent radical nephroureterectomy of nonmetastatic upper urinary tract urothelial carcinoma in 1995 to 2009. We evaluated the impact of bladder cancer on overall mortality and the factors predictive of subsequent bladder cancer. RESULTS: A total of 631 patients (23.7%) had previous or simultaneous bladder cancer. Patients with previous or simultaneous bladder cancer had significantly shorter overall survival than patients without previous or simultaneous bladder cancer (HR 1.29, 95% CI 1.09-1.53, p=0.0026). Of the 2,037 patients without previous or simultaneous bladder cancer 683 (33.5%) subsequently had bladder cancer after radical nephroureterectomy. Of patients with pT0-2 disease those with subsequent bladder cancer had significantly shorter overall survival than patients without subsequent bladder cancer (HR 1.81, 95% CI 1.23-2.67, p=0.0025). In patients with pT3-4 disease subsequent bladder cancer was not associated with worse overall survival. On multivariable analyses independent predictors of subsequent bladder cancer were gender, preoperative urine cytology and clinical node status in the preoperative setting, and gender, adjuvant chemotherapy and pathological node status in the postoperative setting. CONCLUSIONS: Bladder cancer was significantly associated with worse clinical outcomes after radical nephroureterectomy of upper urinary tract urothelial carcinoma. Preventing subsequent bladder cancer in patients with pT0-2 upper urinary tract urothelial carcinoma may lead to better prognosis in those who undergo radical nephroureterectomy.

A randomized phase III trial of denosumab before curettage for giant cell tumor of bone: Japan Clinical Oncology Group Study JCOG1610.

A randomized phase III trial was planned to commence in October 2017. Resectable giant cell tumor of bone (GCTB) without possible postoperative large bone defect has been treated by curettage with local adjuvant treatment, with the local recurrence rate found to be as high as 24.6-30.8%. The aim of this study is to confirm the superiority of preoperative denosumab for patients with GCTB without possible postoperative large bone defect. A total of 106 patients will be accrued from 34 Japanese institutions over 5 years. The primary endpoint is relapse-free survival (RFS). Secondary endpoints include overall survival, joint-preserved survival, local RFS, metastasis-free survival, adverse events, serious adverse events, surgical and postoperative complications, and discontinuation of denosumab. This trial is conducted by the Bone and Soft Tissue Tumor Study Group in the Japan Clinical Oncology Group and has been registered in the UMIN Clinical Trials Registry as UMIN000029451 [http://www.umin.ac.jp/ctr/index.htm].

Randomized phase III study to evaluate the value of omission of prophylactic neck dissection for stage I/II tongue cancer: Japan Clinical Oncology Group study (JCOG1601, RESPOND).

For stage I/II tongue cancer patients, it is controversial whether prophylactic neck dissection should be performed with partial glossectomy. Based on the evidence of the primary tumor's depth of invasion as a predictive factor of occult lymph node metastases and a prognostic factor of disease-free survival, randomized phase III trial was initiated in November 2017 to evaluate the omission value for prophylactic neck dissection for stage I/II tongue cancer with 3-10 mm of depth of invasion. In 5 years, 440 patients will be accrued from 28 institutions. The primary end point of the study is the overall survival, whereas the secondary end points are relapse-free survival, local relapse-free survival, proportion of unresectable relapse and of cervical lymph node relapse, post-operative function (paralysis of the accessory and facial nerves and subjective symptoms) and adverse events. This trial has been registered with the UMIN Clinical Trials Registry (registration number: UMIN000030098; http://www.umin.ac.jp/ctr/index.htm).

A randomized Phase III trial of adjuvant S-1 therapy vs. observation alone in resected biliary tract cancer: Japan Clinical Oncology Group Study (JCOG1202, ASCOT).

No standard adjuvant treatment has been established for patients with curatively resected biliary tract cancer. S-1 has been reported to show promising efficacy with mild toxicity profiles in patients with advanced biliary tract cancer, and adjuvant S-1 therapy has been demonstrated to provide survival benefit in patients with resected gastric cancer and pancreatic cancer. The aim of this open-label, multicenter, randomized Phase III trial is to confirm that adjuvant chemotherapy with S-1 would prolong overall survival in patients with resected biliary tract cancer. This study was activated in September 2013. A total of 350 patients planned to be enrolled from 36 Japanese institutions over a period of 4 years. At July 2017, the protocol was revised to increase power from 70% to 80%. Therefore, the planned total sample size is 440. The primary endpoint is overall survival. This trial is registered with the UMIN Clinical Trials Registry as UMIN000011688.

A Phase III trial of a single early intravesical instillation of pirarubicin to prevent bladder recurrence after radical nephroureterectomy for upper tract urothelial carcinoma (JCOG1403, UTUC THP Phase III).

Observation is the current standard for managing cases of Stage 0a-III upper tract urothelial carcinoma after radical nephroureterectomy. A randomized Phase III trial commenced in Japan during October 2016. The trial is designed to investigate the superiority of a single early intravesical instillation of pirarubicin, compared with observation, in terms of relapse-free survival after radical nephroureterectomy for Stage 0a-III upper tract urothelial carcinoma. During a 5-year period, 310 patients will be recruited from 43 Japanese institutions. The primary endpoint is defined as relapse-free survival, and the secondary endpoints are overall survival, intravesical relapse-free survival, adverse events, and serious adverse events. This trial has been registered in the UMIN Clinical Trials Registry (UMIN000024267, http://www.umin.ac.jp/ctr/index.htm).

Role of lymph node dissection during radical nephroureterectomy for upper urinary tract urothelial cancer: multi-institutional large retrospective study JCOG1110A.

PURPOSE: To evaluate the impact of lymph node dissection (LND) on clinical outcome during radical nephroureterectomy (RNU) for patients with upper urinary tract urothelial cancer (UTUC). METHODS: We, the Urologic Oncology Study Group of the Japan Clinical Oncology Group (JCOG), retrospectively collected data from patients with non-metastatic UTUC who underwent RNU in 30 centers in 1995-2009. Ineligible patients and patients with previous and/or synchronous bladder cancer were excluded, and the remaining 2037 patients were analyzed. We compared overall and cancer-specific mortality between patients who underwent LND (LND group) and those without LND (no-LND group). RESULTS: Among 2037 patients, LND was performed in 1046 (51.4%) patients, and 223 (10.9%) patients had pathological node-positive (pN+) disease. All-cause mortality was observed in 503 patients (24.7%) during follow-up (median 45.8 months), including 363 patients (17.8%) who died of UTUC. Patients with pN+ disease showed significantly shorter overall survival (OS) compared with pN0 patients, and the estimated 5-year OS for pN+ patients was 30%. Older age, ≥cT3, and clinical node-positive disease were found as preoperative predictors for pN+ disease by multivariate analysis. In the comparison of OS and cancer-specific mortality between LND and no-LND groups, there was no significant improvement by LND in multivariate analysis. The median number of lymph nodes removed was six (IQR 3-11). There was no significant association between the number of lymph nodes removed and OS. CONCLUSIONS: The present study indicates that there is no therapeutic benefit of LND during RNU for UTUC, although pathologically positive LN status can predict poor prognosis.

A randomized Phase III trial of comparing two dose-fractionations stereotactic body radiotherapy (SBRT) for medically inoperable Stage IA non-small cell lung cancer or small lung lesions clinically diagnosed as primary lung cancer: Japan Clinical Oncology Group Study JCOG1408 (J-SBRT trial).

A randomized Phase III trial commenced in Japan in February 2016. Currently, 42 Gy in four fractions of stereotactic body radiotherapy prescribed at the D95% of the planning target volume, which is considered equal to the commonly used 48 Gy in four fractions at the isocenter using an old dose calculation algorithm, is the standard treatment in Japan for medically inoperable Stage IA non-small cell lung cancer and small lung lesions clinically diagnosed as primary lung cancer. This study aims to examine the superiority of 55 Gy in four fractions over 42 Gy in four fractions. A total of 750 patients are expected to be accrued in 5 years. The primary endpoint is overall survival and the secondary endpoints are progression-free survival, local progression-free survival, patterns of failure, local control period, adverse events and serious adverse events. This trial is registered at the UMIN Clinical Trials Registry as UMIN000021029 (http://www.umin.ac.jp/ctr/index.htm) the dose covering 95% of the volume (D95%) of the planning target volume.

Stereotactic body radiotherapy versus lobectomy for operable clinical stage IA lung adenocarcinoma: comparison of survival outcomes in two clinical trials with propensity score analysis (JCOG1313-A).

OBJECTIVE: No randomized controlled trials comparing stereotactic body radiotherapy and lobectomy for operable early-stage non-small-cell lung cancer have been successfully conducted. This study compared survival outcomes in two multi-institutional clinical trials for stereotactic body radiotherapy (Japan Clinical Oncology Group JCOG0403) and lobectomy (Japan Clinical Oncology Group JCOG0201) with propensity score analysis. METHODS: Inclusion criteria were operable, cT1N0M0 and adenocarcinoma diagnosed prior to registration of each trial. Forty of 169 patients from JCOG0403 and 219 of 811 patients from JCOG0201 were included. The primary endpoint was overall survival adjusted with propensity score analysis. The patient selection factors included in the logistic model to estimate the propensity score were age, sex, tumor diameter and consolidation/tumor ratio. RESULTS: Among patient selection factors, age distribution was quite different with little overlap: the median was 79 (interquartile range: 74.5-83.5) in stereotactic body radiotherapy and 62 (interquartile range: 55-68) in lobectomy. In propensity score analysis, 21 patients from each group were matched and the hazard ratio for stereotactic body radiotherapy over lobectomy was 9.00 (95% confidence interval: 1.14-71.04). In the post hoc subgroup analysis with propensity score analysis of inverse probability of treatment weighting, patients were limited to be aged 75 or younger because JCOG0201 only included them when aged 75 or younger. Thirteen patients for stereotactic body radiotherapy and 219 for lobectomy were compared, and the hazard ratio for stereotactic body radiotherapy over lobectomy was 1.19 (95% confidence interval: 0.38-3.73). CONCLUSIONS: The point estimates of hazard ratio favored lobectomy over stereotactic body radiotherapy in the limited number of patients. A randomized controlled study is needed for valid comparison.

A Phase II/III study comparing carboplatin and irinotecan with carboplatin and etoposide for the treatment of elderly patients with extensive-disease small-cell lung cancer (JCOG1201).

A randomized Phase II/III trial commenced in Japan in December 2013. Carboplatin plus etoposide is the current standard treatment for elderly extensive-disease small-cell lung cancer. The purpose of this study is to confirm the superiority of carboplatin plus irinotecan in terms of overall survival over carboplatin plus etoposide for elderly extensive-disease small-cell lung cancer patients in a Phase II/III design. A total of 370 patients will be accrued from 38 Japanese institutions within 5 years. In the Phase II part, the primary endpoint is the response rate of the carboplatin plus irinotecan arm and the secondary endpoint is adverse events. In the Phase III part, the primary endpoint is overall survival and the secondary endpoints are progression-free survival, response rate, adverse events, serious adverse events and symptom score. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000012605 (http://www.umin.ac.jp/ctr/index.htm).

A Phase III study of oral steroid administration versus local steroid injection therapy for the prevention of esophageal stricture after endoscopic submucosal dissection (JCOG1217, Steroid EESD P3).

A randomized Phase III trial commenced in Japan in September 2014. Endoscopic local steroid injection has been commonly used and considered acceptable as the current standard treatment for the prevention of esophageal stricture after endoscopic submucosal dissection for superficial esophageal cancer. The purpose of this study is to confirm the superiority of prophylactic oral steroid administration following endoscopic submucosal dissection in terms of stricture-free survival over endoscopic local steroid injection for patients with superficial esophageal cancer. A total of 360 patients will be accrued from 35 Japanese institutions within 2.5 years. The primary endpoint is stricture-free survival, and the secondary endpoints are the number of endoscopic balloon dilations for 12 weeks after endoscopic submucosal dissection, adverse events, serious adverse events and the proportion of patients with dysphagia score ≤1 at 12 weeks after endoscopic submucosal dissection. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000015064 (http://www.umin.ac.jp/ctr/index.htm).

A randomized controlled Phase II/III study comparing endoscopic balloon dilation combined with steroid injection versus radial incision and cutting combined with steroid injection for refractory anastomotic stricture after esophagectomy: Japan Clinical Oncology Group Study JCOG1207.

A randomized Phase II/III trial commenced in May 2014. Endoscopic balloon dilation with steroid injection is the current standard treatment for patients with refractory anastomotic stricture after esophagectomy. The purpose of this study is to confirm the superiority of radial incision and cutting with steroid injection in terms of both restricture-free survival and number of dilations within 24 weeks compared with endoscopic balloon dilation with steroid injection for these patients. A total of 130 patients will be accrued from 30 Japanese institutions over 3 years. The primary endpoint in the Phase II part is proportion of Grade 3/4 intraoperative hemorrhages, post-operative esophageal perforations, esophageal hemorrhages, pneumothorax, lung or mediastinum infections or other unexpected adverse events. Co-primary endpoints in the Phase III part are restricture-free survival and number of dilations within 24 weeks after treatment. Secondary endpoints are proportion of patients with anastomotic diameter >10 mm at 8 weeks after treatment, proportion of adverse events, proportion of patients experiencing improvement of dysphagia score at 2, 4, 8 and 24 weeks after treatment and proportion of patients with dysphagia score ≤1 at 24 weeks after treatment. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000014017 [http://www.umin.ac.jp/ctr/index.htm].

A Phase III trial comparing irinotecan and cisplatin with etoposide and cisplatin in adjuvant chemotherapy for completely resected pulmonary high-grade neuroendocrine carcinoma (JCOG1205/1206).

A randomized Phase III trial commenced in Japan in March 2013. Post-operative adjuvant chemotherapy with etoposide plus cisplatin is the current standard treatment for resected pulmonary high-grade neuroendocrine carcinoma including small cell lung cancer and large cell neuroendocrine carcinoma. The purpose of this study is to confirm the superiority of irinotecan plus cisplatin in terms of overall survival over etoposide plus cisplatin as post-operative adjuvant chemotherapy for pathological Stage I-IIIA completely resected pulmonary high-grade neuroendocrine carcinoma patients. A total of 220 patients will be accrued from 54 Japanese institutions within 6 years. The primary endpoint is overall survival and the secondary endpoints are relapse-free survival, proportion of treatment completion, adverse events, serious adverse events and second malignancy. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000010298 [http://www.umin.ac.jp/ctr/index.htm].

Randomized Phase III Study of Irinotecan Plus Cisplatin Versus Etoposide Plus Cisplatin for Completely Resected High-Grade Neuroendocrine Carcinoma of the Lung: JCOG1205/1206.

PURPOSE: To verify the superiority of irinotecan plus cisplatin over etoposide plus cisplatin as postoperative adjuvant chemotherapy for patients with pathologic stage I-IIIA, completely resected, high-grade neuroendocrine carcinoma (HGNEC) of the lung. METHODS: This was a randomized, open-label, phase III study on patients with completely resected stage I-IIIA HGNEC of the lung. They were randomly assigned to receive either etoposide (100 mg/m2, days 1-3) plus cisplatin (80 mg/m2, day 1) or irinotecan (60 mg/m2, days 1, 8, 15) plus cisplatin (60 mg/m2, day 1) up to four cycles. The primary end point was relapse-free survival (RFS) in the intention-to-treat population. This trial was registered with the Japan Registry of Clinical Trials (jRCTs031180216). RESULTS: Between April 2013 and October 2018, 221 patients were enrolled (etoposide plus cisplatin arm, 111 patients; irinotecan plus cisplatin arm, 110 patients). In the second interim analysis, early termination of the trial was recommended because of futility. At a median follow-up of 24.1 months, the 3-year RFS was 65.4% for etoposide plus cisplatin and 69.0% for irinotecan plus cisplatin, with a hazard ratio of 1.076 (95% CI, 0.666 to 1.738; one-sided log-rank P = .619). Grade 3-4 adverse events were more frequent in the etoposide plus cisplatin arm, with febrile neutropenia (20% of 109 patients v 4% of 107 patients) and neutropenia (97% v 36%) being the most common. Meanwhile, grade 3-4 anorexia (6% v 11%) and diarrhea (1% v 8%) were more frequently observed in the irinotecan plus cisplatin arm. CONCLUSION: Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving RFS in patients with completely resected HGNEC; thus, etoposide plus cisplatin remains the standard treatment.

Dose-finding and efficacy confirmation trial of the superselective intra-arterial infusion of cisplatin and concomitant radiotherapy for locally advanced maxillary sinus cancer (Japan Clinical Oncology Group 1212): Dose-finding phase.

BACKGROUND: We are currently undertaking a multi-institutional prospective trial of the superselective intra-arterial infusion of high-dose cisplatin with concomitant radiotherapy for patients with T4aN0M0 or T4bN0M0 locally advanced maxillary sinus squamous cell carcinomas (SCC). We herein report the results of the dose-finding phase. METHODS: The dose-finding phase sought to evaluate the incidence of dose-limiting toxicities and determine the recommended number of cycles of the intra-arterial infusion of cisplatin. In this phase, 100 mg/m2 of cisplatin was administered intra-arterially weekly for 7 weeks with concomitant radiotherapy (70 Gy). RESULTS: All 18 patients received a full dose of radiotherapy. The number of cycles of cisplatin was 7 in 13 patients and 6 in 5 patients. The dose-limiting toxicities were observed in 5 patients. CONCLUSION: These results indicated that this therapy is safe and well-tolerated at 7 cycles of cisplatin, which was determined to be the recommended number of cycles for locally advanced maxillary sinus SCC.