Prognostic significance of ground-glass areas within tumours in non-small-cell lung cancer.

OBJECTIVES: To validate or refute the hypothesis that non-small-cell lung cancers (NSCLC) with ground-glass areas (GGA+) within the tumour on high-resolution computed tomography are associated with a more favourable prognosis than those without GGA (GGA-). METHODS: We analysed data from a multicentre observational cohort study in Japan including 5005 patients with completely resected pathological stage I NSCLC, who were excluded from the Japan Clinical Oncology Group (JCOG) 0707 trial on oral adjuvant treatment during the enrolment period. The patients' medical and pathological records were assessed retrospectively by physicians and re-staged according to the 8th tumour, node, metastasis edition. RESULTS: Of the 5005 patients, 2388 (48%) were ineligible for the JCOG0707 trial and 2617 (52%) were eligible but were not enrolled. A total of 958 patients (19.1%) died. Patients with GGA+ NSCLC and pathological invasion ≤3 cm showed significantly better overall survival than others. In patients with tumours with an invasive portion ≤4 cm, GGA+ was associated with better survival. The prognoses of patients with GGA+ T2a and GGA- T1c tumours were similar (5-year overall survival: 84.6% vs 83.1%, respectively). The survival with T2b or more tumours appeared unaffected by GGA, and GGA was not prognostic in these larger tumours. CONCLUSIONS: Patients with GGA+ NSCLC on high-resolution computed tomography and ≤4 cm invasion size may have a better prognosis than patients with solid GGA- tumours of the same T-stage. However, the presence or absence of radiological GGA has little impact on the prognosis of patients with NSCLC with greater (>4 cm) pathological invasion.

Multi-institutional study of osimertinib dose-optimization in non-small cell lung cancer patients with EGFR activating mutation aged 70 years or older ('MONEY' trial).

Osimertinib is the standard of care for patients with epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer. Dose-toxicity has been previously reported, but no dose-response data within the range of 20-240 mg daily (mg/d). Thus, the current 80 mg/d dosing might be too high for elderly Japanese patients with an average body weight of only 50 kg, resulting in excessive toxicity and cost. We therefore initiated a study to investigate whether osimertinib at 40 mg/d is non-inferior to 80 mg/d in patients with advanced or recurrent epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer aged ≥70 years, using a regression discontinuity design. Osimertinib is administered at 40 mg/d for body weight ≤50 kg, and 80 mg/d for body weight >50 kg. The primary endpoint is progression-free survival. Sample size is 550 patients, based on a non-inferiority margin of the progression-free survival hazard ratio 1.333, 0.10 one-sided type I error and 80% power.

Association of D-dimer level with thrombotic events, bleeding, and mortality in Japanese patients with solid tumors: a Cancer-VTE Registry subanalysis.

BACKGROUND: The D-dimer test is a simple test frequently used in routine clinical screening for venous thromboembolism (VTE). The Cancer-VTE Registry was a large-scale, multicenter, prospective, observational study in Japanese patients with cancer. This study aimed to clarify the relationship between D-dimer level at cancer diagnosis (baseline) and the incidence of events during cancer treatment (1-year follow-up period). METHODS: This was a post hoc sub-analysis of patients from the Cancer-VTE Registry whose D-dimer levels were measured at baseline. The incidence of events during the 1-year follow-up period was evaluated stratified by baseline D-dimer level. Adjusted hazard ratios for D-dimer level and events during the follow-up period were evaluated. RESULTS: Among the total enrolled patients, baseline D-dimer level was measured in 9020 patients. The mean ± standard deviation baseline D-dimer level was 1.57 ± 3.94 µg/mL. During the follow-up period, the incidence of VTE, cerebral infarction/transient ischemic attack (TIA)/systemic embolic events (SEE), bleeding, and all-cause death increased with increasing baseline D-dimer level. The incidence of all-cause death increased with increasing D-dimer level regardless of cancer stage. The adjusted hazard ratio of all-cause death was 1.03 (95% confidence interval: 1.02-1.03) per 1.0-µg/mL increase in baseline D-dimer level. CONCLUSIONS: Increases in D-dimer levels were associated with a higher risk of thrombotic events, such as VTE and cerebral infarction/TIA/SEE, during cancer treatment. Furthermore, higher D-dimer levels at cancer diagnosis were associated with a higher mortality rate, regardless of cancer stage.

Prospective, Multi-Institutional Observational Study of Deterioration in Activities of Daily Living in Elderly Patients After Lung Cancer Surgery.

Introduction: To determine the rate of deteriorating activities of daily living (ADL) and to investigate predictive factors in elderly patients undergoing surgery for NSCLC. Methods: Patients with NSCLC aged 75 years or older who underwent curative surgical resection were evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence Instrumental ADL (TMIG-IADL) and the Japanese version of EuroQol 5-dimensions 5-level (EQ-5D-5L) quality-of-life scale administered at baseline and at 6 months postoperative. The primary end point was the rate of living patients without substantial deterioration of TMIG-IADL, defined as a decline greater than or equal to three points. Multivariable logistic regression was performed to determine risk factors for deteriorating ADL. Results: Between May 2019 and May 2020, 876 of the 986 screened patients enrolled from 47 institutions were eligible and included in the analysis. TMIG-IADL and EQ-5D-5L scores were obtained from 96.0% and 92.6% of the patients, respectively. At 6 months postoperative, 745 patients (85.1%, 95% confidence interval: 82.5%-87.3%) reported no significant ADL deterioration, and 96 of 841 patients (11.4%) with postoperative score data reported significant deterioration. The social domain was the most frequently affected activity. In multivariable analysis, poor performance status, low G8 geriatric screening score, segmentectomy (versus wedge resection), and surgery lasting less than 3 hours were associated with deteriorating ADL. Worsening EQ-5D-5L scores by minimally important difference or more were observed in 22.1% of the patients. Changes in TMIG-IADL and EQ-5D-5L scores were poorly correlated. Conclusions: Approximately 15% of elderly patients with NSCLC experienced significant ADL deterioration at 6 months postoperative.

Quality of life with docetaxel plus cisplatin versus paclitaxel plus carboplatin in patients with completely resected non-small cell lung cancer: quality of life analysis of TORG 0503.

PURPOSE: The TORG0503 study was undertaken to select a preferred platinum-based third-generation regimen for patients with completely resected non-small cell lung cancer (NSCLC). This study aimed to describe the quality of life (QOL) analysis of that study. METHODS: Patients with completely resected NSCLC were randomized to receive three cycles of docetaxel plus cisplatin (DC) or paclitaxel plus carboplatin (PC) on day 1 every 3 weeks. QOL was assessed at three time points (baseline, after two cycles, and after three cycles) using the Functional Assessment of Cancer Therapy-taxane (FACT-Taxane). The adjusted odds ratio (OR) and 95% confidence interval (CI) were calculated by logistic regression analysis that was adjusted for the baseline score in the FACT-Taxane total score and each subscale to evaluate treatment (PC vs. DC) effectiveness. RESULTS: QOL data from 104 patients (DC, n = 56 patients; PC, n = 48) were analyzed. In the FACT-Taxane total score, the baseline-adjusted OR (95% CI) of not worse QOL for the DC group was 3.3 (1.4-8.3) compared with the PC group. In the taxane subscale, the baseline-adjusted OR (95% CI) was 6.2 (2.6-16.0). CONCLUSION: Total QOL was maintained better in the DC group than in the PC group, especially the taxane subscale that consists of neurotoxicity and taxane components in spite of no treatment-related death in both arms between DC and PC. We might recommend DC as the control regimen for the next clinical trial from the viewpoint of QOL, similar to the primary outcomes in TORG0503.

Observational study to predict the efficacy and optimal duration of nivolumab treatment in patients with previously treated advanced or recurrent non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors, including nivolumab, are essential agents for treating non-small cell lung cancer. However, predictive markers are currently lacking, especially using factors based on patient-reported outcomes. METHODS: We conducted a prospective observational study of 244 patients with advanced or recurrent non-small cell lung cancer treated with second- or later-line nivolumab from August 2016 to December 2017. Patient-reported outcomes, including quality of life, were evaluated by the EQ-5D-5L before and during nivolumab treatment. To predict the efficacy of nivolumab during the early treatment phase, we also analyzed the patients' clinical characteristics, responses and immune-related adverse events at 9 weeks of therapy. The primary endpoint was the disease control rate at 25 weeks after the initiation of nivolumab. RESULTS: The objective response and disease control rates at 25 weeks were 18.5 and 41.2%, respectively. The emergence of immune-related adverse events at 9 weeks did not significantly affect the disease control rate at 6 months. The response at 9 weeks and patient-reported quality of life were potentially predictive of disease control at week 25. Disease control on week 9 and patients-reported outcomes were potential predictive factors for the overall survival. CONCLUSIONS: This study found no new baseline factors predicting the outcome of nivolumab treatment in patients with non-small cell lung cancer, but response to nivolumab was a robust predictor of overall efficacy. In addition, patient-perceived quality of life could predict the durable efficacy of immune checkpoint inhibitors.

Association between tumor response to systemic therapy and patient-reported disease symptoms.

BACKGROUND: The association of treatment-induced tumor shrinkage with symptom palliation for patients with lung cancer remains unknown. We investigated this correlation using the Edmonton Symptom Assessment System-Revised. METHODS: Using the in-hospital cancer registry, we identified patients receiving chemotherapy and/or immunotherapy for newly diagnosed advanced or metastatic lung cancer. Tumor response and post-treatment Edmonton Symptom Assessment System-Revised were obtained after 2-3 treatment cycles. Patients were divided into groups with or without >30% unidirectional tumor shrinkage (objective response [OR] or non-OR [N-OR] groups, respectively). They were further classified as good-objective response (>50% unidirectional tumor shrinkage), moderate-objective response (30-50% shrinkage), progressive disease (>20% tumor growth or new lesion) or stable disease (SD; N-objective response and non-progressive disease). The primary endpoint was change in the total Edmonton Symptom Assessment System-Revised score from baseline. The Mann-Whitney U test was used for analysis. RESULTS: In total, 113 patients were enrolled. The total Edmonton Symptom Assessment System-Revised score was significantly more improved in the OR group versus the N-OR group (median: 5 vs. 2, respectively; P = 0.013). This association was more prominent in patients with small-cell lung cancer and large-cell neuroendocrine tumor than those with other histology. Sensitivity analyses showed that the total Edmonton Symptom Assessment System-Revised score was more improved in the OR group versus the SD group (median: 5 vs. 3, respectively; P = 0.029) and in the 'good-OR' group versus the 'moderate-OR and SD' group (median: 7.5 vs. 2, respectively; P = 0.003), suggesting that greater tumor shrinkage led to more symptom amelioration. CONCLUSIONS: Tumor shrinkage was associated with Edmonton Symptom Assessment System-Revised score improvement in patients with lung cancer receiving systemic therapy.

One-Year Incidences of Venous Thromboembolism, Bleeding, and Death in Patients With Lung Cancer (Cancer-VTE Subanalysis).

Introduction: This subanalysis aimed to provide real-world data on venous thromboembolism (VTE) from patients with lung cancer in the Cancer-VTE Registry. Methods: The primary outcome was the number of baseline VTE events in patients with lung cancer. The 1-year cumulative incidences of symptomatic VTE; composite VTE (symptomatic and incidental VTE requiring treatment); bleeding; cerebral infarction, transient ischemic attack, and systemic embolic events; and all-cause death were calculated. Clinical trial registration: UMIN000024942. Results: The study enrolled a total of 2377 patients with lung cancer; of these, 119 (5.0%) had VTE (six [0.3%], symptomatic, and 113 [4.8%], asymptomatic) and 14 (0.6%) had pulmonary embolism at baseline. During the follow-up period (mean, 337.7 d), the incidence was 0.6% for symptomatic VTE, 1.8% for composite VTE, 1.5% for bleeding events, 1.3% for cerebral infarction, transient ischemic attack, and systemic embolism, and 19.1% for all-cause death. Composite VTE frequency did not vary by anticancer drug type. Patients with (versus without) VTE at baseline had higher hazard ratios (HRs) for composite VTE (unadjusted HR: 5.29; Gray test p < 0.001) and symptomatic VTE (unadjusted HR: 4.89; Gray test p = 0.007). Patients with VTE at baseline had higher HRs for bleeding events (unadjusted HR: 3.27; Gray test p = 0.010) and all-cause death (unadjusted HR: 2.73; log-rank test p < 0.001) than patients without. In multivariable analysis, patients with baseline VTE prevalence and Eastern Cooperative Oncology Group Performance Status of 2 had increased composite VTE risk during cancer therapy. There were no other risk factors for composite VTE. Conclusions: Our findings emphasize the importance of VTE screening at cancer diagnosis.

Efficacy of Adjuvant Chemotherapy With Tegafur-Uracil in Patients With Completely Resected, Node-Negative NSCLC-Real-World Data in the Era of Molecularly Targeted Agents and Immunotherapy.

Introduction: In Japan, adjuvant tegafur-uracil (UFT) chemotherapy is recommended for patients with completely resected, stage I NSCLC. This treatment requires real-world re-evaluation because of recent advances in target-based and immuno-oncological treatments and refinement of lung cancer staging. Methods: The Japan Clinical Oncology Group (JCOG) 0707, a phase 3 trial comparing the benefits of UFT and S-1 (tegafur-gimeracil-oteracil) in patients with completely resected stage I NSCLC (T1 >2 cm and T2 in the TNM sixth edition), was conducted in Japan. A multicenter observational cohort study (Comprehensive Support Project for Oncology Research [CSPOR]-LC03) was also conducted for those patients excluded from JCOG 0707 during the study enrollment period. Physicians from institutions that participated in JCOG 0707 retrospectively assessed the medical records of each patient. The efficacy of UFT was evaluated in the CSPOR-LC03 cohort. Results: In the entire study population (n = 5005), patients treated with UFT (n = 1549) had significantly longer overall survival (OS) than those without any adjuvant chemotherapy (n = 3338). There was no significant difference in OS between the patients treated with UFT (n = 1061) and those without adjuvant chemotherapy (n = 1484) in the JCOG 0707-eligible population (logrank p = 0.755). For tumors without ground-glass attenuation and size greater than 3 cm, patients treated with UFT had significantly longer survival than those without adjuvant chemotherapy, on univariate but not on multivariate analysis. Conclusions: There was no significant difference in OS between the patients treated with UFT and those without adjuvant chemotherapy in the clinical trial-eligible population. Adjuvant UFT for patients with completely resected NSCLC may be recommended only in patients with a tumor without ground-glass attenuation and size greater than 3 cm. In patients with node-negative early NSCLC, further study is needed to select patients who will benefit from adjuvant chemotherapy.

One-year incidence of venous thromboembolism, bleeding, and death in patients with solid tumors newly initiating cancer treatment: Results from the Cancer-VTE Registry.

INTRODUCTION: Although many publications have reported the incidence of venous thromboembolism (VTE) in patients with cancer from Western countries, to date, no prospective East Asian studies have been published, and potential racial differences remain unclear. The multicenter, prospective, observational Cancer-VTE Registry aimed to clarify the incidence of VTE and bleeding and identify risk factors in Japanese patients with solid tumors after one year of follow-up. MATERIALS AND METHODS: Patients with colorectal, lung, stomach, pancreatic, breast, or gynecologic cancer were enrolled after VTE screening and before starting cancer treatment. The follow-up period was one year. The main outcomes were the incidences of symptomatic VTE, bleeding events (major or clinically relevant non-major), and all-cause death, evaluated according to VTE presence/absence at baseline. Multivariate analyses were conducted to identify risk factors for events. RESULTS: Among 9630 patients, the one-year cumulative incidences of symptomatic VTE, bleeding events, and all-cause death were 0.5%, 1.4%, and 12.2%, respectively. The majority of VTEs identified at baseline were asymptomatic distal deep vein thromboses; however, affected patients had higher event rates during the follow-up period. The most important independent risk factor for developing symptomatic VTE, bleeding events, and death during the follow-up period was the presence of symptomatic or asymptomatic VTE at baseline. CONCLUSIONS: These data have revealed the incidence of symptomatic VTE in Japanese patients with solid tumors during one year of follow-up. The presence of any VTE before initiating cancer treatment was an independent risk factor for symptomatic VTE, bleeding events, and death during subsequent treatment.

Final report on plasma ctDNA T790M monitoring during EGFR-TKI treatment in patients with EGFR mutant non-small cell lung cancer (JP-CLEAR trial).

Osimertinib is active against T790M-positive epidermal growth factor receptor mutant non-small cell lung cancer. We enrolled 122 sensitive epidermal growth factor receptor mutant non-small cell lung cancer patients who were planned to receive or were receiving first-/second-generation epidermal growth factor receptor tyrosine kinase inhibitors without disease progression and monitored plasma T790M every 1-2 months using the cobas® EGFR Mutation Test v2. We previously reported the concordance between T790M status in plasma and tissue. This is the final report on the sensitivity of plasma T790M and the efficacy of sequential osimertinib. The sensitivity was 21.1% (95% confidence interval: 6.1-45.6%). The best overall response was 25.0% (95% confidence interval: 9.8-46.7) in the plasma T790M-positive group and 28.6% (95% confidence interval: 8.4-58.1) in the plasma T790M-negative but tissue T790M-positive group. Median progression-free survival was 7.9 months (95% confidence interval: 4.7-17.5) for the former and 4.4 months (95% confidence interval: 3.0-N.E.) for the latter, with no statistically significant difference (P = 0.74).

Efficacy and safety of first-line osimertinib treatment and postprogression patterns of care in patients with epidermal growth factor receptor activating mutation-positive advanced non-small cell lung cancer (Reiwa study): study protocol of a multicentre, real-world observational study.

INTRODUCTION: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is widely used as the first-line treatment for EGFR mutation-positive non-small cell lung cancer (NSCLC). Nevertheless, most cases ultimately acquire resistance to osimertinib, and no effective treatment has been currently established for cases having progressive disease (PD) with osimertinib. In clinical practice, EGFR-TKI therapy could be continued beyond response evaluation criteria in solid tumours (RECIST)-defined PD cases when they are clinically stable. Currently, the progression pattern of osimertinib and criteria for identifying patients who might benefit from osimertinib beyond PD are unknown. In addition, the efficacy and safety of osimertinib as the first-line treatment in real-world clinical practice remain unclear in Japan. This multicentre study was designed to evaluate the real-world data on first-line osimertinib and its post-treatment. METHODS AND ANALYSIS: The study enrols patients with EGFR mutation-positive, advanced or recurrent NSCLC who received EGFR-TKI as the first-line therapy after 1 September 2018, from October 2019 to August 2020, and those started on osimertinib will be followed up until August 2022. We will evaluate the efficacy and safety of the first-line osimertinib treatment, adherence to it, progression patterns on RECIST PD and subsequent treatment. ETHICS AND DISSEMINATION: All participating patients will provide written informed consent before entering the study. The protocol, amendments and patients' informed consent forms will be approved before study commencement by the institutional review board or independent ethics committee at each participation site (Lead Ethics Committee; Japan Red Cross Medical Center (26 April 2019, order number 976)). Patients will be anonymised before registration into the study and their anonymised data will be collected from the case report form. The results of this study will be presented at the national and international conferences and submitted for publication. TRIAL REGISTRATION NUMBER: UMIN000038683.

Medical costs of Japanese lung cancer patients during end-of-life care.

OBJECTIVE: The medical costs associated with cancer treatment have increased rapidly in Japan; however, little data exist on actual costs, especially for end-of-life care. Therefore, this study aimed to examine the medical costs of lung cancer patients during the last 3 months before death and to compare the costs with those of initial anticancer treatment. METHODS: We retrospectively evaluated all patients who died from lung cancer at the Japanese Red Cross Medical Center between 1 January 2008 and 31 August 2019. Patients were classified into three cohorts (2008-2011, 2012-2015 and 2016-2019) according to the year of death; the medical costs were evaluated for each cohort. Costs were then divided into outpatient and inpatient costs and calculated per month. RESULTS: Seventy-nine small cell lung cancer and 213 non-small cell lung cancer patients were included. For small cell lung cancer and non-small cell lung cancer patients, most end-of-life medical costs were inpatient costs across all cohorts. The median monthly medical costs for the last 3 months among both small cell lung cancer and non-small cell lung cancer patients did not differ significantly among the cohorts, but the mean monthly costs for non-small cell lung cancer tended to increase. The monthly medical costs for the last 3 months were significantly higher than those for the first year in SCLC (P = 0.013) and non-small cell lung cancer (P < 0.001) patients and those for the first 3 months in non-small cell lung cancer patients (P = 0.005). CONCLUSIONS: The medical costs during the end-of-life period for lung cancer were high and surpassed those for initial treatment.

Medical costs of lung cancer care in Japan during the first one or two years after initial diagnosis.

OBJECTIVES: Japan's healthcare expenditures, especially on oncology, are rapidly growing; however, there are scant data on actual costs and cost-effectiveness in the real world. The aim was to assess the medical costs and outcomes of patients with advanced lung cancer. METHODS: We retrospectively investigated all patients who were diagnosed with advanced lung cancer at the Japanese Red Cross Medical Center between 1 January 2008 and 31 December 2018. Patients were classified into three cohorts according to the year of diagnosis-Cohort 1: 2008-2010, Cohort 2: 2011-2014 and Cohort 3: 2015-2018-and assessed for medical costs and outcome. Medical costs were divided into outpatient and inpatient costs and were calculated on a monthly basis. RESULTS: Ninety-five patients with small cell lung cancer (SCLC) and 330 with nonsmall cell lung cancer (NSCLC) were included. There was a trend toward increased costs during the first two years after diagnosis in NSCLC patients, without changes in monthly costs, reflecting improved survival. Compared to Cohort 1, Cohort 3 patients with NSCLC had longer survival (median: 24 versus 12 months, P < 0.001), with a median incremental cost of Japanese Yen 6 million during the initial two years. The proportion of outpatient costs increased over time, especially for NSCLC patients (P < 0.001). No changes in costs or survival were observed in SCLC patients. CONCLUSIONS: In NSCLC patients, medical costs increased with prolonged survival during the last decade. The costs on a monthly basis did not change. The proportion of outpatient costs increased.