Protocol for a prospective multicenter randomized controlled trial to evaluate the efficacy of texture and color enhancement imaging (TXI) observation in the detection of colorectal lesions (deTXIon study).

Colonoscopy is the gold standard for detecting and resecting adenomas or early stage cancers to reduce the incidence and mortality rates of colorectal cancer. In a recent observational study, texture and color enhancement imaging (TXI) was reported to improve polyp detection during colonoscopy. This randomized controlled trial involving six Japanese institutions aims to confirm the superiority of TXI over standard white-light imaging (WLI) in detecting colorectal lesions during colonoscopy. During the 1-year study period, 960 patients will be enrolled, with 480 patients in the TXI and WLI groups. The primary endpoint is the mean number of adenomas detected per procedure. The secondary endpoints include adenoma detection rate, advanced adenoma detection rate, polyp detection rate, flat polyp detection rate, depressed lesion detection rate, mean polyps detected per procedure, sessile serrated lesion (SSL) detection rate, mean SSLs detected per procedure and adverse events.

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.

Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial.

Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

Progress report of a cross-organ and biomarker-based basket-type clinical trial: BELIEVE Trial.

Cancer genomic medicine using next-generation sequencers has been developing. However, the number of patients who could receive genomically matched therapy is limited because off-label use or patient-oriented compassionate use was not permitted under National Health Insurance in Japan. To improve patient drug accessibility, we initiated a biomarker-based basket-type clinical trial (NCCH1901) in October 2019 under patient-proposed healthcare services. We listed the drugs that had high medical needs but were not covered by National Healthcare Insurance. Then we included these drugs before patient proposal so that they could access off-label drugs soon after they had the results of CGP tests. All drugs were provided free of charge by pharmaceutical companies. The objective was to administer off-label drugs and to collect efficacy and safety data for these drugs. The primary endpoint was the response rate based on the best overall response for up to 16 weeks. As of January 31, 2022, we included 18 drug cohorts and 295 patients were treated in this study. The most common cancer was brain tumor, followed by carcinoma of endocrine organs and colorectal cancer. BRAF mutations and ERBB2 amplifications were the frequent genomic abnormalities to be enrolled. This study was one way to access off-label drugs, and contributed significantly to providing treatment opportunities for patients in Japan.

Platform trial for off-label oncology drugs using comprehensive genomic profiling under the universal public healthcare system: the BELIEVE trial.

BACKGROUND: Precision medicine has transformed cancer treatment by focusing on personalized approaches based on genomic abnormalities. However, comprehensive genomic profiling (CGP) and access to targeted therapies are limited in Japan. This study investigates the BELIEVE trial, which aims to improve drug accessibility for patients with actionable genetic abnormalities through off-label drug administration. METHODS: The BELIEVE trial is a platform trial with a single master protocol, conducted under the Clinical Trials Act and the patient-proposed health services (PPHS) scheme. Eligible patients with solid tumors exhibiting actionable alterations were enrolled, and CGP tests covered by national health insurance were employed. Treatment selection, study drugs from collaborating pharmaceutical companies, and treatment schedules adhered to predefined protocols. Primary and secondary endpoints were evaluated, and statistical analysis was conducted based on patient response rates. RESULTS: The BELIEVE trial offered treatment opportunities for patients with relapse/refractory disease who lacked standard therapies or clinical trial options. This study addresses unmet medical needs and contributes to the establishment of precision medicine systems. Similar trials like NCI-MATCH and TAPUR are being conducted globally. The BELIEVE trial provides a platform for off-label drug administration, collects essential clinical data, and contributes to drug approval applications. CONCLUSION: The BELIEVE trial provides hope for patients with actionable genetic abnormalities by facilitating access to targeted therapies through off-label drug administration. It establishes a regulatory framework and promotes collaboration between industry and academia by expanding organ-specific and cross-organ biomarker-based treatments.

Final analysis of a randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311).

OBJECTIVE: To assess the efficacy of dose-dense weekly paclitaxel plus carboplatin in metastatic or recurrent cervical carcinoma, we conducted a phase II/III randomized controlled study comparing dose-dense paclitaxel and carboplatin with or without bevacizumab to conventional paclitaxel and carboplatin with or without bevacizumab. However, at the primary analysis of the phase II part, the response rate in the dose-dense arm was not higher than in the conventional arm and the study was terminated early before starting phase III. After a further 2 years of follow-up, we conducted this final analysis. METHODS: 122 patients were enrolled and randomly assigned to either the conventional or dose-dense arm. After bevacizumab was approved in Japan, patients in both arms received bevacizumab if not contraindicated. In the final analysis, overall survival, progression-free survival, and adverse events were updated. RESULTS: The median follow-up of surviving patients was 34.8 months (range 19.2-64.8). Median overall survival in the conventional arm was 17.7 months and in the dose-dense arm 18.5 months (p=0.71). Median progression-free survival in the conventional arm was 7.9 months and in the dose-dense arm 7.2 months (p=0.64). A platinum-free interval within 24 weeks and treatment without bevacizumab were identified as prognostic factors for overall and progression-free survival. Grade 3 to 4 non-hematologic toxicity occurred in 46.7% of patients who received the conventional regimen and in 43.3% of patients who received the dose-dense regimen. Adverse events related to bevacizumab in 82 patients included fistula in five (6.1%) and gastrointestinal perforation in three (3.7%). CONCLUSIONS: It was confirmed that dose-dense paclitaxel plus carboplatin for metastatic or recurrent cervical carcinoma is not superior to conventional paclitaxel and carboplatin. Patients who had early refractory disease after prior chemoradiotherapy had the poorest prognosis. The development of treatments that improve the prognosis of such patients remains an important issue. CLINICAL TRIAL INFORMATION: jRCTs031180007.

Robust automated prediction of the revised Vienna Classification in colonoscopy using deep learning: development and initial external validation.

BACKGROUND: Improved optical diagnostic technology is needed that can be used by also outside expert centers. Hence, we developed an artificial intelligence (AI) system that automatically and robustly predicts the pathological diagnosis based on the revised Vienna Classification using standard colonoscopy images. METHODS: We prepared deep learning algorithms and colonoscopy images containing pathologically proven lesions (56,872 images, 6775 lesions). Four classifications were adopted: revised Vienna Classification category 1, 3, and 4/5 and normal images. The best algorithm-ResNet152-in the independent internal validation (14,048 images, 1718 lesions) was used for external validation (255 images, 128 lesions) based on neoplastic and non-neoplastic classification. Diagnostic performance of endoscopists was compared using a computer-assisted interpreting test. RESULTS: In the internal validation, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for adenoma (category 3) of 84.6% (95% CI 83.5-85.6%), 99.7% (99.5-99.8%), 90.8% (89.9-91.7%), 89.2% (88.5-99.0%), and 89.8% (89.3-90.4%), respectively. In the external validation, ResNet152's sensitivity, specificity, PPV, NPV, and accuracy for neoplastic lesions were 88.3% (82.6-94.1%), 90.3% (83.0-97.7%), 94.6% (90.5-98.8%), 80.0% (70.6-89.4%), and 89.0% (84.5-93.6%), respectively. This diagnostic performance was superior to that of expert endoscopists. Area under the receiver-operating characteristic curve was 0.903 (0.860-0.946). CONCLUSIONS: The developed AI system can help non-expert endoscopists make differential diagnoses of colorectal neoplasia on par with expert endoscopists during colonoscopy. (229/250 words).

Evaluation of breast cosmetic changes with a computer-software; the breast cancer conservative treatment cosmetic results (BCCT. core) in hypofractionated whole breast irradiation after breast-conserving surgery-supplementary analysis of multicenter single-arm confirmatory trial: JCOG0906.

BACKGROUND: A good cosmetic outcome has been defined as an important endpoint in breast-conserving therapy (BCT). Various evaluation methods have been studied, but the optimal method has yet to be identified. The present supplementary analysis of JCOG0906 focused on comparing evaluation methods for breast cosmetic outcomes following hypofractionated whole breast irradiation (HFWBI) to examine whether a computer-software (the Breast Cancer Conservative Treatment cosmetic results [BCCT. core])-based program evaluation (CE) can be used for Asian women in clinical trials of BCT. METHODS: Of 306 women, 292 underwent institutional evaluation (IE) for breast cosmetic outcomes before (pre) and 3 years after (post) HFWBI using a 4-point scale (excellent/good/fair/poor), and they were evaluated by CE and a central panel evaluation (PE) on the same scale using 292 pairs of pre/post-HFWBI photographs. PE was performed twice by consensus of the same two experts with a 3-year interval. CE was assessed individually by two radiation oncologists, an expert and a non-expert. Intra-observer variability and inter-observer variability were calculated using the kappa (k) and weighted kappa (wk) statistics. RESULTS: The agreement between the first and second PE using pre/post-HFWBI photographs was moderate (k = 0.60, wk = 0.64. k = 0.53, wk = 0.60). The agreement between the expert and non-expert on CE was substantial (k = 0.72, wk = 0.76. k = 0.72, wk = 0.77). The inter-observer variability of CE was smaller than the intra-observer variability of PE. CONCLUSION: CE with BCCT. core was considered a reproducible and an appropriate evaluation method for Asian women in clinical trials of BCT, when breast cosmetic changes were compared between pre/post therapy.

Effectiveness of Favipiravir on Nonsevere, Early-Stage COVID-19 in Japan: A Large Observational Study Using the COVID-19 Registry Japan.

INTRODUCTION: Several randomized controlled trials have compared the effectiveness of favipiravir with that of placebo. However, evidence regarding its effect on nonsevere, early-stage coronavirus disease 2019 (COVID-19) remains insufficient. METHODS: We used the COVID-19 Registry Japan, a nationwide registry of inpatients with COVID-19, for evaluating the effectiveness of favipiravir on patients with nonsevere, early-stage COVID-19. Eligible patients, who did not need supplementary oxygen therapy at admission, were classified according to two regimens (starting favipiravir therapy within 4 days from admission vs. no favipiravir during hospitalization) and were then compared using a three-step method (cloning, censoring, and weighting). The primary outcome was supplementary oxygen requirement during hospitalization, and the secondary outcomes were the need for invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO) and overall mortality at 30 days. RESULTS: A total of 7654 cases were analyzed. The "start favipiravir" regimen did not show substantial differences in the primary outcome [hazard ratio 0.825, 95% confidence interval (CI) 0.657-1.04, p = 0.098] and both of the secondary outcomes [need for IMV/ECMO and overall 30-day mortality, hazard ratio 1.02 (95% CI 0.649-1.60) and 0.869 (95% CI 0.519-1.46), p = 0.929 and 0.594, respectively]. CONCLUSIONS: In this large cohort from a COVID-19 registry, favipiravir was not associated with a positive effect on the clinical outcome on patients with nonsevere, early-stage COVID-19, suggesting that it is not an essential drug for COVID-19 treatment.

Clinical characteristics of the first three waves of hospitalised patients with COVID-19 in Japan prior to the widespread use of vaccination: a nationwide observational study.

Background: Before widespread coronavirus disease (COVID-19) vaccinations, Japan experienced three COVID-19 epidemic waves. This study aimed to evaluate the characteristics of hospitalised COVID-19 patients and reveal temporal changes. Methods: This study included 33,554 hospitalised patients with COVID-19 from 553 healthcare facilities. Data were analysed by age group and epidemic wave (first wave, 01/01/2020-05/31/2020; second wave, 06/01/2020-10/31/2020; and third wave, 11/01/2020-03/31/2021). Findings: By age group, 3% (under 18), 22% (young), 34% (middle-aged), and 41% (older patients) were aged 0-17, 18-39, 40-64, and >65 years; while 16%, 35%, and 49% were in the first, second, and third wave, respectively. The patients' overall median age (58 years; interquartile range, 39-74) was lowest and highest during the second and third waves, respectively. The frequency of any comorbidity was lowest and highest during the second (44·5%) and third (63·6%) waves, respectively. The symptoms at admission and exposure history differed considerably with age. The overall case fatality rate (5%) was highest among older patients (11·4%). Case fatality rate was highest and lowest during the first (7·3%) and second (2·8%) waves, respectively. Medication use changed over time. Interpretation: Although the overall case fatality rate remained relatively low, it was more than twice as high among older patients. After adjusting for age and comorbidities, the risk of death was highest in the first wave. Funding: This work was supported by the Ministry of Health, Labour and Welfare "Research on Emerging and Re-emerging Infectious Diseases and Immunization" 19HA1003].

Topical corticosteroid therapy for facial acneiform eruption due to EGFR inhibitors in metastatic colorectal cancer patients: a randomized controlled trial comparing starting with a very strong or a weak topical corticosteroid (FAEISS study, NCCH1512, colorectal part).

BACKGROUND: Although pre-emptive therapy with oral tetracycline, moisturizer, sunscreen, and topical corticosteroid is useful for preventing acneiform eruption (AfE) due to epidermal growth factor receptor (EGFR) inhibitors, no studies have examined the efficacy of topical corticosteroids themselves, or investigated the optimal potency of corticosteroid for treating facial AfE (FAfE). PATIENTS AND METHODS: Screened patients with RAS wild-type colorectal cancer started pre-emptive therapy with oral minocycline and moisturizer on initiation of cetuximab or panitumumab therapy. Patients who developed grade 1 or 2 FAfE were randomly allocated to two groups: a ranking-down (RD) group that started with a very strong corticosteroid and serially ranked down every 2 weeks unless FAfE exacerbated; and a ranking-up (RU) group that started with a weak corticosteroid and serially ranked up at exacerbation. FAfE grade, patient quality of life, and adverse events (AEs) with topical corticosteroid were evaluated every 2 weeks. The primary endpoint was the total number of times grade 2 or higher FAfE was identified in the central review of the 8-week treatment period. RESULTS: No significant differences in total numbers of grade 2 or higher FAfE or in AEs caused by topical corticosteroids were observed between groups during the 8 weeks. Incidence of grade 2 or higher FAfE tended to be lower in the RD group during the first 2 weeks. CONCLUSION: Considering the long-term care of FAfE, the RU regimen appears suitable and should be considered the standard treatment for FAfE due to EGFR inhibitor therapy. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000024113).

Effectiveness of remdesivir in hospitalized nonsevere patients with COVID-19 in Japan: A large observational study using the COVID-19 Registry Japan.

OBJECTIVES: To evaluate the effectiveness of remdesivir in the early stage of nonsevere COVID-19. Although several randomized controlled trials have compared the effectiveness of remdesivir with that of a placebo, there is limited evidence regarding its effect in the early stage of nonsevere COVID-19 cases. METHODS: We evaluated the effectiveness of remdesivir in the early stage of nonsevere COVID-19 using the COVID-19 Registry Japan, a nationwide registry of hospitalized patients with COVID-19 in Japan. Two regimens ("start remdesivir" therapy within 4 days from admission versus no remdesivir during hospitalization) among patients without the need for supplementary oxygen therapy were compared by a 3-step processing (cloning, censoring, and weighting) method. The primary outcome was a supplementary oxygen requirement during hospitalization. Secondary outcomes were 30-day in-hospital mortality and the risk of invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO). The data of 12,487 cases met our inclusion criteria. The "start remdesivir" regimen showed a lower risk of supplementary oxygen requirement (hazard ratio [HR]: 0.850, 95% confidence interval [CI]: 0.798-0.906, p value < 0.001). Both 30-day in-hospital mortality and risk of IMV/ECMO introduction were not significantly different between the 2 regimens (HRs: 1.04 and 0.983, 95% CI: 0.980-1.09 and 0.906-1.07, p values: 0.210 and 0.678, respectively). CONCLUSIONS: Remdesivir might reduce the risk of oxygen requirement during hospitalization in the early stage of COVID-19; however, it had no positive effect on the clinical outcome and reduction in IMV/ECMO requirement.

Survey Results and Recommendations from Japanese Stakeholders for Good Clinical Practice Renovation.

BACKGROUND: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is undertaking a major revision of ICH E6 Good Clinical Practice (GCP) decided to involve external stakeholders in ICH-GCP renovation. Activities such as surveys and public conferences have taken place in the United States, European Union, and Japan. For stakeholder engagement in Japan, a designated research group conducted a survey of academic stakeholders. METHODS: A total of 105 academic stakeholders from 18 institutions responded to the survey. The research group developed recommendations reflecting the survey results and the opinions from patients and the public. RESULTS: The survey showed the top four principles needing renovation were (i) informed consent (Chapter 2.9, 12.4% of respondents believed it needed renovation), (ii) systems for quality assurance (Chapter 2.13, 9.5%), (iii) information on an investigational product (Chapter 2.4, 5.7%), and (iv) procedures on clinical trial information (Chapter 2.10, 5.7%). The top three sections identified as needing renovation were: (i) informed consent (Chapter 4.8, 27.6%), (ii) monitoring (Chapter 5.18, 22.9%), and (iii) composition, functions, and operations of the ethics committee (Chapter 3.2, 14.3%). Recommendations included clarification of ICH-GCP's scope, proportionality in various aspects of clinical trials, diversity and liquidity of ethics committee members, modernization of informed consent procedures, variations in monitoring, and regulatory grade when using real-world data. CONCLUSION: The recommendations from Japanese investigators and patients have been submitted to the ICH E6 Expert Working Group, which will strengthen the robustness of the GCP renovation.

Study protocol for NCCH1908 (UPFRONT-trial): a prospective clinical trial to evaluate the feasibility and utility of comprehensive genomic profiling prior to the initial systemic treatment in advanced solid tumour patients.

Comprehensive genomic profiling has been approved for use in patients with advanced solid tumours; however, it is only indicated in advanced solid tumour patients without available standard chemotherapeutic treatment or those who have completed standard treatments in Japan, and there are no available data on the clinical feasibility and utility of comprehensive genomic profiling in treatment-naive patients. This multicentre, single-arm, prospective study aims to evaluate the feasibility and utility of the OncoGuide NCC Oncopanel System in treatment-naive patients with six advanced major malignancies: non-small cell lung cancer, breast cancer, gastric cancer, colon cancer, pancreatic cancer and biliary tract cancer (NCCH1908). This study (study cohort) will be compared with the other prospective observational study (control cohort), which enrols patients not receiving comprehensive genomic profiling prior to initial systemic treatment. A total of 200 patients will be enrolled in the study over 21 months. This study has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (UMIN000040743). CLINICAL TRIAL REGISTRATION: This study, initiated in June 2020, has been registered in the UMIN Clinical Trials Registry (www.umin.ac.jp/ctr/) (registration number: UMIN000040743). We plan to enrol a total of 200 patients over a period of 21 months.

Evaluation of the efficacy of anticoagulation therapy in reducing mortality in a nationwide cohort of hospitalized patients with coronavirus disease in Japan.

OBJECTIVES: To determine whether anticoagulation therapy improves outcomes in patients with coronavirus disease 2019 (COVID-19) in Japan given their lower risk of thrombosis compared with Western cohorts. METHODS: The efficacy of anticoagulation therapy in hospitalized patients with COVID-19 was evaluated using a nationwide registry: the COVID-19 Registry Japan. The inverse probability of weight treatment method was used to adjust for baseline confounders in the anticoagulation and non-anticoagulation groups. RESULTS: Of the 1748 patients included, anticoagulants were used in 367 patients (treatment group). The patients in the anticoagulant group were older, predominantly male, and often presented with obesity, hyperlipidaemia, hypertension, diabetes and elevated D-dimer levels. Twenty-nine-day mortality was 7.6% in the whole cohort (treatment group, 11.2%; no treatment group, 6.6%), 6% in patients who were not treated with steroids (treatment group, 12.3%; no treatment group, 5.2%), and 11.2% in patients treated with steroids (treatment group, 10.5%; no treatment group, 11.8%). Mortality in the whole cohort was similar between the treatment and no treatment groups (P=0.99), and an insignificant decreasing trend in mortality was observed in patients treated with steroids (P=0.075). CONCLUSIONS: Anticoagulants may be beneficial in Asians, in whom comorbidities and risk of thrombosis may differ from other ethnic groups.

A randomized phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab and docetaxel in elderly patients with advanced stage HER2-positive breast cancer: Japan Clinical Oncology Group Study (JCOG1607, HERB TEA study).

The standard first-line treatment for patients with human epidermal growth factor 2-positive metastatic breast cancer is a combination therapy of trastuzumab, pertuzumab and docetaxel, and the standard second-line treatment is trastuzumab emtansine. However, it may be difficult for the elderly to maintain sufficient intensity of treatment due to severe adverse events of trastuzumab, pertuzumab and docetaxel. The aim of this trial is to confirm the non-inferiority of trastuzumab emtansine over trastuzumab, pertuzumab and docetaxel in terms of overall survival in elderly (65-year-old or more) patients with human epidermal growth factor 2-positive metastatic breast cancer. If improved overall survival and fewer toxicities are observed, trastuzumab emtansine may be a feasible new standard first-line treatment for elderly patients with human epidermal growth factor 2-positive metastatic breast cancer. A planned total 330 patients will be enrolled from 45 institutions over 6.5 years. This trial has been registered in the UMIN Clinical Trials Registry as UMIN000030783 [http://www.umin.ac.jp/ctr/index.htm].

A randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311): Primary analysis.

OBJECTIVE: To assess the efficacy and safety of dose-dense weekly paclitaxel plus carboplatin (ddTC) with or without bevacizumab compared to conventional, tri-weekly paclitaxel plus carboplatin (cTC) with or without bevacizumab, in metastatic or recurrent cervical carcinoma not amenable to curative local therapy. METHODS: Patients were randomly assigned to either the cTC or ddTC arm. The cTC regimen was paclitaxel 175 mg/m2 and carboplatin at an area under the curve (AUC) of 5 on day 1. The ddTC regimen was paclitaxel 80 mg/m2 on day 1, 8, 15 and carboplatin at AUC of 5 on day 1. Both cTC and ddTC treatments were repeated every 3 weeks for up to 9 cycles. After bevacizumab was approved in Japan, patients in both arms received bevacizumab 15 mg/kg if not contraindicated. The primary endpoint of phase II part was response rate (RR). If the RR of ddTC+bevacizumab was found to be at least 5% better than to cTC + bevacizumab, the study would proceed to phase III part, which had overall survival as its primary endpoint. CLINICAL TRIAL INFORMATION: jRCTs031180007. RESULTS: In total, 122 patients were randomly assigned to either the cTC arm (cTC + bevacizumab: 32; cTC:29) or the ddTC arm (ddTC+bevacizumab: 30; ddTC:31). The RR for patients on cTC + bevacizumab was 67.9%, and for patients on ddTC+bevacizumab 60.7%, cTC: 55.2%, and ddTC: 50.0%. CONCLUSIONS: The study did not meet the primary endpoint of phase II portion. Dose-dense, weekly paclitaxel plus carboplatin is not promising for metastatic or recurrent cervical carcinoma.

Results of the non-small cell lung cancer part of a phase III, open-label, randomized trial evaluating topical corticosteroid therapy for facial acneiform dermatitis induced by EGFR inhibitors: stepwise rank down from potent corticosteroid (FAEISS study, NCCH-1512).

PURPOSE: This FAEISS study was designed to confirm the superior efficacy of reactive topical corticosteroid strategies employing serially ranking-DOWN from very strong steroid levels for the treatment of facial acneiform rash induced by epidermal growth factor receptor (EGFR) inhibitors (EGFRIs), in comparison with strategies employing serially ranking-UP from weak steroid levels. This article reports the primary results of the non-small cell lung cancer (NSCLC) part of the trial. METHODS: Patients with EGFR-mutated advanced NSCLC treated with erlotinib or afatinib were enrolled in the first registration. All patients received preemptive therapy with oral minocycline and heparinoid moisturizer from the initiation of an EGFR inhibitor. Enrolled patients who developed facial acneiform rash within 2 weeks were randomized at second registration to either a ranking-UP (WEAK) group or a ranking-DOWN group. The primary endpoint was incidence of grade ≥ 2 facial acneiform rash over 8 weeks. RESULTS: Fifty-one patients were enrolled at the first registration and received EGFRIs (n = 30 for afatinib, n = 21 for erlotinib). However, 35 patients did not develop facial acneiform rash within 2 weeks; one patient discontinued preemptive treatment. Fifteen patients (29.4%) were enrolled in the second registration; nine were assigned to the WEAK group and six to the DOWN group. There was no significant difference in the incidence of grade ≥ 2 facial acneiform rash between the WEAK group (one patient, twice) and the DOWN group (one patient, twice; p = 0.8417). No patients developed severe facial acneiform rash within 10 weeks. CONCLUSION: In NSCLC patients who received EGFRIs, preemptive therapy of oral minocycline and heparinoid moisturizer reduced facial acneiform rash incidence. TRIAL REGISTRATION: UMIN000024113.

Clinical Epidemiology of Hospitalized Patients With Coronavirus Disease 2019 (COVID-19) in Japan: Report of the COVID-19 Registry Japan.

BACKGROUND: There is limited understanding of the characteristics of patients with coronavirus disease 2019 (COVID-19) requiring hospitalization in Japan. METHODS: This study included 2638 cases enrolled from 227 healthcare facilities that participated in the COVID-19 Registry Japan (COVIREGI-JP). The inclusion criteria for enrollment of a case in COVIREGI-JP are both (1) a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test and (2) inpatient treatment at a healthcare facility. RESULTS: The median age of hospitalized patients with COVID-19 was 56 years (interquartile range [IQR], 40-71 years). More than half of cases were male (58.9%, 1542/2619). Nearly 60% of the cases had close contact to confirmed or suspected cases of COVID-19. The median duration of symptoms before admission was 7 days (IQR, 4-10 days). The most common comorbidities were hypertension (15%, 396/2638) and diabetes without complications (14.2%, 374/2638). The number of nonsevere cases (68.2%, n = 1798) was twice the number of severe cases (31.8%, n = 840) at admission. The respiratory support during hospitalization includes those who received no oxygen support (61.6%, 1623/2636) followed by those who received supplemental oxygen (29.9%, 788/2636) and invasive mechanical ventilation/extracorporeal membrane oxygenation (8.5%, 225/2636). Overall, 66.9% (1762/2634) of patients were discharged home, while 7.5% (197/2634) died. CONCLUSIONS: We identified the clinical epidemiological features of COVID-19 in hospitalized patients in Japan. When compared with existing inpatient studies in other countries, these results demonstrated fewer comorbidities and a trend towards lower mortality.