齋藤 合

INTRODUCTION: Osimertinib is a highly effective first-line treatment for advanced epithelial growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). With its expanded perioperative use, the long-term risk of cardiotoxicity merits investigation. We assessed the occurrence and risk factors of QT prolongation and cardiac dysfunction in patients with NSCLC treated with first-line osimertinib across multiple institutions. METHODS: This retrospective cohort study, a part of the OSI-FACT study, included 538 patients who started first-line osimertinib treatment between August 2018 and December 2019. Patients receiving concurrent anticancer therapies were excluded. Clinical data, including patient characteristics, EGFR mutation status, and tumor stage, were analyzed. Cardiotoxicity graded per Common Terminology Criteria for Adverse Events version 5.0 was monitored via ECG and echocardiography over a median follow-up of 37 months. RESULTS: QT prolongation occurred in 23 patients (4.3 %), with eight reaching Grade ≥3. The median time to onset was 246 days. No significant risk factors for QT prolongation were identified. Cardiac dysfunction was reported in 14 patients (2.6 %), with five cases of Grade ≥3. The median onset was 171 days, with cases occurring after six months. Multivariate analysis identified poor performance status as a risk factor for cardiac dysfunction (HR 2.24, p = 0.005). CONCLUSION: Osimertinib-related cardiotoxicity, while rare, has important clinical implications, particularly for older patients and those with comorbidities. Regular monitoring, beyond the first year, is essential to ensure patient safety.

INTRODUCTION: Stage IV non-small cell lung carcinoma (NSCLC) with oligometastases is potentially curable by radical treatment. This study aimed to evaluate the efficacy and safety of chemoradiotherapy (CRT) for thoracic disease, including the primary lesion and lymph node metastases, combined with local consolidative therapy (LCT) for oligometastases. METHODS: This was a multicenter Phase II trial for patients with Stage IV NSCLC with oligometastases for whom CRT for thoracic disease was feasible. The treatment procedures included CRT containing platinum-doublet for thoracic disease and LCT for oligometastases within 8 weeks of starting or completing CRT. The primary endpoint was the 2-year survival rate. RESULTS: We enrolled 19 patients between June 2016 and May 2020. The median age was 68 (range: 51-74) years. Twelve patients had adenocarcinoma, and 6 had squamous cell carcinoma. The metastasis sites included the brain, bone, adrenal gland, lung, and cervical lymph node (n = 9, 7, 2, 1, and 1, respectively). All patients completed CRT concurrently with LCT for all oligometastases. There were 11 partial responses, resulting in a response rate of 58% (95% confidence interval [CI] 33.5-79.7%). Median progression-free survival and overall survival were 8.6 (95% CI 7.0-10.2) and 42.1 (80% CI 13.6-not reached) months, respectively. The 2-year survival rate was 68.4% (80% CI 52.6%-79.9%). Fourteen patients (74%) showed progression with newly observed lesions. There were no severe adverse events, and toxicities were tolerable. CONCLUSION: Chemotherapy in combination with aggressive LCT for NSCLC with oligometastases might extend survival and achieve local control. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network, Japan (protocol identification number: UMIN000022431, first registration date: 01/JUN/2016).

BACKGROUND: The clinical impact of hypomagnesemia induced by necitumumab plus gemcitabine and cisplatin (GCN) as a second-line or later therapy is unclear. OBJECTIVE: We aimed to evaluate the clinical characteristics and survival impact of hypomagnesemia induced by this therapy. DESIGN: This was a sub-analysis of the retrospective multicenter NINJA study. METHODS: Among the 93 patients enrolled in the NINJA study, this subanalysis included 75 patients with baseline serum magnesium concentrations. RESULTS: The incidence of grade ⩾2 hypomagnesemia was 18.0% in the patients with normal baseline serum magnesium concentrations and 42.8% in those with low concentrations (p = 0.073). The discontinuation rates of GCN treatment owing to hypomagnesemia in each group were 0% and 7.1%, respectively (p = 0.187). The number of necitumumab doses and severity of hypomagnesemia were positively correlated (r = 0.389, p < 0.001). Patients who developed hypomagnesemia in fewer than 21 days after the first dose of GCN (n = 12) had significantly poorer progression-free survival (PFS) than those without the condition (n = 63; median: 4.1 vs 4.4 months, p = 0.048). A similar trend was observed for OS (median: 9.7 vs 15.7 months, p = 0.062). These results were maintained after multivariate analyses (PFS: hazard ratio (HR) 2.46, p = 0.014; OS: HR 2.78, p = 0.021). CONCLUSION: GCN as a second-line or later therapy may be tolerable regardless of the patient's baseline serum magnesium concentration. On the other hand, early serum magnesium reduction with this therapy is associated with a poor prognosis. However, caution should be needed because our results lacked sufficient information for confounding variables other than those analyzed here that may influence the correlation between hypomagnesemia and survival.

In clinical clerkship (CC), medical students can practice evidence-based medicine (EBM) with their assigned patients. Although CC can be a valuable opportunity for EBM education, the impact of EBM training, including long-term behavioral changes, remains unclear. One hundred and nine fourth- and fifth-year medical students undergoing CC at a medical school in Japan attended a workplace-based learning program for EBM during CC (WB-EBM), which included the practice of the five steps of EBM. The program's effect on the students' attitudes toward EBM in CC was assessed through questionnaires. A total of 88 medical students participated in the program. Responses to the questionnaire indicated high satisfaction with the WB-EBM program. The most common theme in students' clinical problems with their assigned patients was the choice of treatment, followed by its effect. Based on the responses in the post-survey for the long-term effects of the program, the frequency of problem formulation and article reading tended to increase in the 'within six months' group comprising 18 students who participated in the WB-EBM program, compared with the control group comprising 34 students who did not. Additionally, the ability to self-assess problem formulation was significantly higher, compared with the control group. However, among 52 students who participated in the WB-EBM program more than six months later, EBM-related behavioral habits in CC and self-assessments of the five steps of EBM were not significantly different from those in the control group. The WB-EBM program was acceptable for medical students in CC. It motivated them to formulate clinical questions and enhanced their critical thinking. Moreover, the WB-EBM program can improve habits and self-evaluations about EBM. However, as its effects may not last more than six months, it may need to be repeated across departments throughout CC to change behavior in EBM practice.

BACKGROUND: Chemoimmunotherapy is the standard first-line treatment for extensive-stage small-cell lung cancer (ES-SCLC); however, its real-world long-term outcomes associated with patient backgrounds are still unclear. We explored this association using an updated large real-world prospective cohort with a minimum follow-up of 3 years. METHODS: This prospective cohort study, conducted across 32 hospitals, enrolled patients with ES-SCLC receiving carboplatin, etoposide, and atezolizumab between September 1, 2019 and September 30, 2020. Updated data with a minimum 3-year follow-up period were analyzed. Patients who met eligibility criteria for pivotal phase 3 clinical trials were considered "trial-eligible." RESULTS: The median (range) time from the treatment initiation to data cutoff (September 30, 2023) was 42.2 (35.8-48.2) months for the enrolled 207 patients. Most patients (89 %) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients fulfilling the inclusion criteria (132 [64 %]) were categorized as trial-eligible. The 3-year progression-free survival (PFS) probability and overall survival (OS) were 6.1 % and 20.9 %, respectively. The 3-year OS probabilities for trial-eligible and trial-ineligible patients were 26.7 and 9.5 %, respectively. The trial-eligible cohort had a larger percentage of patients achieving a 3-year OS (30/132, 22.7 %) than the trial-ineligible cohort (5/75, 6.7 %) (P = 0.003) CONCLUSIONS: Our study provides the first documentation of the long-term outcomes following chemoimmunotherapy in a large prospective real-world cohort of patients with ES-SCLC. Key eligibility criteria significantly influenced the long-term effectiveness. These findings provide valuable insights into the practical effectiveness of chemoimmunotherapy and clinical decision-making for patients with ES-SCLC.