Transitional dynamics in oncology clinical trials: evaluating the impact of Clinical Trials Act on cooperative groups.

OBJECTIVE: large-scale multicentre clinical trials conducted by cooperative groups have generated a lot of evidence to establish better standard treatments. The Clinical Trials Act was enforced on 1 April 2018, in Japan, and it has remarkably increased the operational burden on investigators, but its long-term impact on cancer cooperative groups is unknown. METHODS: a survey was conducted across the nine major cooperative groups that constitute the Japan Cancer Trials Network to assess the impact of Clinical Trials Act on the number of newly initiated trials from fiscal year (from 1 April to 31 March) 2017 to 2022 and that of ongoing trials on 1 April in each year from 2018 to 2023. RESULTS: the number of newly initiated trials dropped from 38 trials in fiscal year 2017 to 26 trials in fiscal year 2018, surged to 50 trials in fiscal year 2019, but then gradually decreased to 25 trials by fiscal year 2022. Specified clinical trials decreased from 32 trials in fiscal year 2019 to 12 trials in fiscal year 2022. The number of ongoing trials was 220 trials in 2018, peaked at 245 trials in 2020, but then gradually decreased to 219 trials by 2023. The number of specified clinical trials has been in consistent decline. By April 2023, of the 20 ongoing non-specified clinical trials, nine adhered to Clinical Trials Act and 11 followed the Ethical Guidelines for Medical and Health Research Involving Human Subjects. CONCLUSION: the number of multicentre clinical trials in oncology gradually decreased after the Clinical Trials Act's enforcement, which underscores the need for comprehensive amendment of the Clinical Trials Act to streamline the operational process.

Clinical characteristics of patients with B-cell lymphoma enrolled in clinical trials for aggressive lymphoma in Japan: Japan Clinical Oncology Group - Lymphoma Study Group study - JCOG0108A.

The clinical characteristics of B-cell lymphoma (BCL) were studied through the combined analysis of six clinical trials conducted by the Japan Clinical Oncology Group - Lymphoma Study Group (JCOG-LSG) for aggressive lymphoma in the 1990s, before the introduction of rituximab. Through a central pathological review, 829 patients were diagnosed with BCL according to the World Health Organization classification and treated with doxorubicin-containing combination chemotherapies. Of these patients, 642, 104, 30, and 24 patients were diagnosed with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL), respectively. The overall survival (OS) of FL and MZL patients was higher than that of patients with DLBCL and MCL. The OS of the MCL patients was higher than that of DLBCL patients in the first 5 years, but MCL had the lowest survival after 5 years. The OS of DLBCL patients was clearly stratified by the international prognostic index and showed data compatible with that of aggressive lymphoma in the pre-rituximab era. These results established the clinical aspects of BCL in a large number of patients treated in prospective studies during the pre-rituximab era in Japan.

Pretreatment total serum protein is a significant prognostic factor for the outcome of patients with peripheral T/natural killer-cell lymphomas.

Peripheral T- and NK-cell lymphomas (PT/NKCLs) are relatively rare, and few studies have validated the International Prognostic Index (IPI) for PT/NKCLs in prospective clinical trials. Histopathological specimens from 136 patients, enrolled in six prospective multicenter trials of doxorubicin-containing regimens, with PT/NKCLs were reviewed by six hematopathologists following the WHO classification. This combined analysis demonstrated that the IPI was not predictive of prognosis for patients with PT/NKCLs as previously shown by GELA. In a univariate analysis, low total serum protein (TP) and albumin levels, gastrointestinal tract involvement, and histologic subtype (extranodal NK/T-cell lymphoma, nasal type, and peripheral T-cell lymphoma, unspecified) were significantly associated with reduced survival. In a multivariate analysis, TP (p = 0.004) and histologic subtype (p = 0.024) remained significant. We discuss the need to establish the importance and meaning of TP and to develop new strategies for patients with PT/NKCLs allowing for TP, especially with worse histologic subtypes.

Prognostic analysis and a new risk model for Hodgkin lymphoma in Japan.

The Japan Clinical Oncology Group conducted two multicenter phase II trials in 200 patients with advanced Hodgkin lymphoma (HL) in the 1990s. Among 181 patients whose histopathological specimens were available and reviewed by 6 hematopathologists, 167 (92.3%) were diagnosed with HL. Five-year overall survival (OS) among these 167 patients was 88.3%, including 89.2% among nodular sclerosis and 82.2% among mixed cellularity cases. International prognostic score was not closely associated with OS. Seven unfavorable prognostic factors for OS on univariate analysis were male, B symptoms, clinical stage of III or IV, elevated serum LDH, elevated alkaline phosphatase, elevated beta2-microglobulin, and pathological subtype (mixed cellularity and lymphocyte depletion). On multivariate analysis, male [HR 3.30 (95% CI 1.15-9.52, p = 0.027)] and elevated serum LDH [HR 2.41 (95% CI 1.07-5.43, p = 0.034)] were independent factors for OS. Based on these prognostic factors, the 5-year OS was 95.7% in the low-risk group (no adverse factor), 87.9% in the intermediate-risk group (1 adverse factor) and 73.3% in the high-risk group (2 adverse factors). This simple prognostic model for HL warrants further validation studies.

[Reliability at the National Cancer Institute-Common Toxicity Criteria version 2.0].

We evaluated the reliability of CTC v 2.0 based on source documents and also studied the degree of inconsistency in toxicity grading. Five clinical research coordinators from the National Cancer Center Hospital independently reviewed source documents from 17 patients and graded toxicities in the following common adverse events: diarrhea, nausea, stomatitis/pharyngitis, vomiting, febrile neutropenia, infection, infection unknown source, and sensory neuropathy. If grading was already documented on the medical chart, it was masked so that the coordinator could perform the evaluation without information bias. After the completion of toxicity grading, the participating coordinators discussed each case, and a consensus was reached for final toxicity grading. The proportion of agreement for each toxicity criteria are as follows: diarrhea; 0.59 (95%CI 0.35-0.82), nausea; 0.47 (0.23-0.71), stomatitis/pharyngitis; 0.59 (0.35-0.82), vomiting; 0.71 (0.49-0.92), febrile neutropenia; 0.88 (0.73-1.04), infection; 0.82 (0.64-1.01), infection by unknown source; 0.82 (0.64-1.01), sensory neuropathy; 0.65 0.42-0.87). The cause of variability largely depended on the differences in individual clinical assessment, and misunderstanding of toxicity criteria by coordinators has been observed. Even in a single institution environment, variability exists in the toxicity assessment and grading. Good training and education on toxicity assessment using common criteria and development of translated manual, including the interpretation of criteria assessment, may help reduce variability.