Osimertinib in Elderly Patients with Epidermal Growth Factor Receptor T790M-Positive Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment: A Phase II Trial.

LESSONS LEARNED: Non-small-cell lung cancer (NSCLC) represents 85% of lung cancer in elderly patients.In the present study performed in the 36 elderly subjects with epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, osimertinib 80 mg demonstrated statistically significant improvement in the objective response rate, which was comparable to those in the nonelderly population.Osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation; further research in larger scale is warranted. BACKGROUND: Previous findings suggest the possibility of relatively safe use of osimertinib for patients with T790M-positive non-small-cell lung cancer (NSCLC), with few serious adverse events for the elderly in comparison with conventional endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and with an antitumor effect. METHODS: This phase II study was performed to prospectively investigate the efficacy and safety of osimertinib for elderly patients aged ≥75 years with ineffective prior EGFR TKI treatment or with recurrence in T790M EGFR TKI resistance mutation-positive NSCLC. RESULTS: A total of 36 patients were included in the analyses. Among the 36 subjects, 63.9% were female, with mean age of 79.9 years. The objective response rate (ORR) was 58.3% (95% confidence interval [CI], 42.2%-72.9%), demonstrating statistically significant efficacy of osimertinib (p = .0017). The median duration of response (DOR) was 27.9 weeks (95% CI, 21.1-82.0). Complete response (CR) and partial response (PR) were 2.8% and 55.6%, respectively. Disease control rate (DCR) was 97.2%. A waterfall plot revealed that 33 (91.6%) subjects exhibited tumor shrinkage during treatment, including 12 of 14 subjects who had stable disease (SD). All adverse events were not reason for discontinuation of the study drug. CONCLUSION: Osimertinib may be an effective and safe treatment option in elderly patients with advanced NSCLC with EGFR mutation.

A randomized phase II study of nutritional and exercise treatment for elderly patients with advanced non-small cell lung or pancreatic cancer: the NEXTAC-TWO study protocol.

BACKGROUND: Most advanced elderly cancer patients experience fatigue, anorexia, and declining physical function due to cancer cachexia, for which effective interventions have not been established. We performed a phase I study of a new nonpharmacological multimodal intervention called the nutritional and exercise treatment for advanced cancer (NEXTAC) program and reported the excellent feasibility of and compliance with this program in elderly patients with advanced cancer who were at risk for cancer cachexia. We report here the background, hypothesis, and design of the next-step multicenter, randomized phase II study to evaluate the efficacy of the program, the NEXTAC-TWO study. METHODS: Patients with chemo-naïve advanced non-small cell lung cancer or pancreatic cancer, age ≥ 70 years, performance status ≤2, with adequate organ function and without disability according to the modified Katz index will be eligible. In total, 130 participants will be recruited from 15 Japanese institutions and will be randomized into either the intervention group or a control group. Computer-generated random numbers are allocated to each participant. Stratification factors include performance status (0 to 1 vs. 2), site of primary cancer (lung vs. pancreas), stage (III vs. IV), and type of chemotherapy (cytotoxic vs. others). Interventions and assessment will be performed 4 times every 4 ± 2 weeks from the date of randomization. Interventions will consist of nutritional counseling, nutritional supplements (rich in branched-chain amino acids), and a home-based exercise program. The exercise program will include low-intensity daily muscle training and lifestyle education to promote physical activity. The primary endpoint is disability-free survival. It is defined as the period from the date of randomization to the date of developing disability or death due to any cause. This trial also plans to evaluate the improvements in nutritional status, physical condition, quality of life, activities of daily living, overall survival, and safety as secondary endpoints. Enrollment began in August 2017. The study results will demonstrate the efficacy of multimodal interventions for elderly cancer patients and their application for the maintenance of physical and nutritional conditions in patients with cancer cachexia. This work is supported by a grant-in-aid from the Japan Agency for Medical Research and Development. DISCUSSION: This is the first randomized trial to evaluate the efficacy and safety of a multimodal intervention specific for elderly patients with advanced cancer. TRIAL REGISTRATION: Registered at August 23, 2017. Registry number: UMIN000028801 .

Changes in serum transforming growth factor-beta concentration as a predictive factor for radiation-induced lung injury onset in radiotherapy-treated patients with locally advanced lung cancer.

Background: Radiation-induced lung injury (RILI) occurs after chest radiation therapy, which ranges from acute radiation pneumonia to subsequent radiation pulmonary fibrosis. However, they are difficult to predict. The study aimed to examine the predictive utility of serum levels of transforming growth factor-beta (TGF-ß) for radiation-induced lung injury. Methods: This single-center prospective observational study enrolled 21 patients with locally advanced lung cancer who underwent chest radiation therapy. We measured the serum levels of TGF-ß, Krebs von Denlungen-6, and granulocyte colony-stimulating factor (GCSF) eight times immediately before irradiation. Results: Seven, four, eight, and one patient had Grade 0, 1, 2, and 3 radiation-induced lung injury, respectively. Compared with the Grade 0 and 1 RILI groups (RP- group), the Grade 2 and 3 RILI groups (RP+ group) had a significantly higher relative ratio of TGF-ß values from immediately before irradiation to the time of 30-48 Gy irradiation (P=0.011). The cut-off value of the TGF-ß relative ratio of the RP+ group measured from the receiver operating characteristic curve was 1.31; moreover, the sensitivity, specificity, and positive predictive value were 75%, 100%, and 75%, respectively. There was no significant between-group difference in the levels of the other cytokines. Conclusions: For patients undergoing radiation therapy for locally advanced lung cancer, the ratio of TGF-ß levels before and after 30-48 Gy irradiation may predict the onset of RILI. Our findings may facilitate the identification of predictors of the onset of radiation-induced lung injury.

Prognostic factors in older patients with wild-type epidermal growth factor receptor advanced non-small cell lung cancer: a multicenter retrospective study.

BACKGROUND: Over 40% Japanese patients with lung cancer are above 75 years of age. A specific strategy to treat such older patients is necessary because most trials exclude older patients with poor physical health. Herein, we aimed to identify predictive factors associated with overall survival (OS) in older patients by evaluating patient backgrounds and laboratory data before the start of treatment. METHODS: This multicenter retrospective medical chart review study was conducted at three Japanese institutions and involved patients aged 75 years and above with epidermal growth factor receptor (EGFR) mutation-negative advanced non-small cell lung cancer (NSCLC). Of the patients, 75 had received best supportive care (BSC) and 49 mono-chemotherapy or platinum-doublet chemotherapy, including immune checkpoint inhibitors (ICIs). OS after diagnosis was analyzed using the Kaplan-Meier survival analysis. Cox proportional hazard models, which included age, Eastern Cooperative Oncology Group performance status (ECOG PS), staging, serum albumin levels, and receipt of chemotherapy were analyzed. RESULTS: Age at diagnosis was not shown to be related to OS in patients receiving BSC. In patients aged 81 years and above, the chemotherapy group tended to have longer survival than did the BSC group, but there was no statistically significant difference in the median OS between the two groups due to the very small number of subjects (n: 30 vs. 12, median: 52 vs. 30 weeks, hazard ratio: 0.512, 95% confidence interval: 0.232-1.130, P=0.088). The patients' performance status and albumin levels at lung cancer diagnosis had the highest impact on OS in the BSC group. CONCLUSIONS: Careful consideration should be given to the indications of chemotherapy for patients aged 81 years and above with wild-type EGFR advanced non-small lung cancer.

Education Program for Male Patients with Chronic Obstructive Pulmonary Disease to Change Dietary Behavior.

Patients with chronic obstructive pulmonary disease (COPD) need to maintain proper eating behavior in order to maintain muscle mass and prevent weight loss. In this study, we measured the effects of a support program on patient attitude, social influences, and self-efficacy and aimed to positively change their dietary behavior. We recruited male patients from two Japanese outpatient clinics and assigned each to an intervention or a control group. The intervention group participated in a support program and was assisted in acquiring knowledge and skills related to adopting and maintaining suitable eating behavior. Data were gathered through medical records, patient interviews, self-assessment questionnaires, and anthropometric measurements. The follow-up period was approximately 15 weeks. The final sample comprised 22 participants, with 11 each in the intervention and control groups. In the intervention group, the body weight was maintained. However, there were statistically significant improvements in energy intake and dietary measures such as eating fresh foods, compared with the control group. The intervention was observed to increase both meal suitability and energy intake among participants. Future support programs should also incorporate participants' physical activity levels, and the effects should be studied over a longer period.

Serum immune modulators during the first cycle of anti-PD-1 antibody therapy in non-small cell lung cancer: Perforin as a biomarker.

BACKGROUND: Currently used biomarkers for immunotherapy are inadequate because they are only based on tumor properties. In view of microenvironment changes by tumors, host immunity should be considered, which may result in identifying more accurate and easily detectable biomarkers for daily clinical practice. Here, we assessed serum immune-modulating factor levels for the response to anti-PD-1 antibodies during the first cycle in non-small cell lung cancer (NSCLC) patients. METHODS: Serum was collected from patients with advanced NSCLC treated with nivolumab or pembrolizumab at several time points during the first cycle. We applied the enzyme-linked immunosorbent assays (ELISAs) and multiplex assays to measure the levels of immune modulators. RESULTS: A total of 40 patients treated with nivolumab and 26 patients treated with pembrolizumab were studied. By ELISA, serum perforin, but not granzyme B, was measured in all samples. By multiplex assay, 10 immune modulators, including granzyme B, were measured in some, but not all, samples. Serum baseline perforin levels were strongly associated with increased progression-free survival (PFS) and overall survival (OS) times. Sequential changes in perforin levels during the first cycle were weakly associated with the clinical outcome. CONCLUSIONS: Serum baseline perforin levels may be used to predict the prognosis of NSCLC patients treated with anti-PD-1 antibody therapy. KEY POINTS: To identify a useful predictive marker for anti-PD-1 antibody therapy, using blood samples might be helpful. Serum baseline perforin levels were closely associated with prognosis with anti-PD-1 antibody therapy in non-small cell lung cancer.

The Quality of Life of Patients with Suspected Lung Cancer before and after Bronchoscopy and the Effect of Mirtazapine on the Depressive Status.

Objective Patients with suspected lung cancer often experience adverse side effects such as anxiety, depression, and a decreased appetite. These side effects influence the patients' quality of life and their ability to make decisions concerning appropriate treatment. This study examined the psychological status and quality of life of patients with suspected lung cancer before and after bronchoscopy treatment and evaluated the effect of mirtazapine prescribed to patients with depression. Methods To assess patient characteristics (e.g. age, gender, and medical history), a questionnaire including the Hospital Anxiety and Depression Scale - Japanese version and the Functional Assessment of Cancer Therapy-L was administered. Patients Forty-three patients admitted for bronchoscopy treatment between May 2017 and April 2018 were included. Results The results showed that patients with depression reported a worse quality of life than those without depression. Compared with no medication, the administration of mirtazapine alleviated depressive symptoms. Furthermore, the patients' depressive status was affected by their physical symptoms, including coughing, tightness of chest, and dyspnea. Conclusion Our results emphasize the importance of detecting depression in the early stages of a cancer diagnosis and have significant implications concerning pharmacological intervention in patients with cancer displaying signs of depression.

Final Results from a Phase II Trial of Osimertinib for Elderly Patients with Epidermal Growth Factor Receptor t790m-Positive Non-Small Cell Lung Cancer That Progressed during Previous Treatment.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in older patients. This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were ≥75 years old and had experienced relapse or progression after previous EGFR-TKI treatment. Our previous report that enrolled 36 patients showed the overall response rate (58.3%) and disease control rate (97.2%), while this report describes the results for the progression-free survival (PFS), overall survival (OS), and safety analyses. The median PFS was 11.9 months (95% confidence interval (CI): 7.9-17.5), and the median OS was 22.0 months (95% CI: 16.0 months-not reached). The most frequent adverse events were anemia/hypoalbuminemia (27 patients, 75.0%), thrombocytopenia (21 patients, 58.3%), and paronychia/anorexia/diarrhea/neutropenia (15 patients, 41.7%). Pneumonitis was observed in four patients (11.1%), including two patients (5.6%) with Grade 3-4 pneumonitis. These results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment, even among patients who were ≥75 years old.

Feasibility of early multimodal interventions for elderly patients with advanced pancreatic and non-small-cell lung cancer.

BACKGROUND: Combinations of exercise and nutritional interventions might improve the functional prognosis for cachectic cancer patients. However, high attrition and poor compliance with interventions limit their efficacy. We aimed to test the feasibility of the early induction of new multimodal interventions specific for elderly patients with advanced cancer Nutrition and Exercise Treatment for Advanced Cancer (NEXTAC) programme. METHODS: This was a multicentre prospective single-arm study. We recruited 30 of 46 screened patients aged ≥70 years scheduled to receive first-line chemotherapy for newly diagnosed, advanced pancreatic, or non-small-cell lung cancer. Physical activity was measured using pedometers/accelerometer (Lifecorder® , Suzuken Co., Ltd., Japan). An 8 week educational intervention comprised three exercise and three nutritional sessions. The exercise interventions combined home-based low-intensity resistance training and counselling to promote physical activity. Nutritional interventions included standard nutritional counselling and instruction on how to manage symptoms that interfere with patient's appetite and oral intake. Supplements rich in branched-chain amino acids (Inner Power® , Otsuka Pharmaceutical Co., Ltd., Japan) were provided. The primary endpoint of the study was feasibility, which was defined as the proportion of patients attending ≥4 of six sessions. Secondary endpoints included compliance and safety. RESULTS: The median patient age was 75 years (range, 70-84). Twelve patients (40%) were cachectic at baseline. Twenty-nine patients attended ≥4 of the six planned sessions (96.7%, 95% confidence interval, 83.3 to 99.4). One patient dropped out due to deteriorating health status. The median proportion of days of compliance with supplement consumption and exercise performance were 99% and 91%, respectively. Adverse events possibly related to the NEXTAC programme were observed in five patients and included muscle pain (Grade 1 in two patients), arthralgia (Grade 1 in one patient), dyspnoea on exertion (Grade 1 in one patient), and plantar aponeurositis (Grade 1 in one patient). CONCLUSIONS: The early induction of multimodal interventions showed excellent compliance and safety in elderly patients with newly diagnosed pancreatic and non-small-cell lung cancer receiving concurrent chemotherapy. We are now conducting a randomized phase II study to measure the impact of these interventions on functional prognosis.

Promotion of Behavioral Change and the Impact on Quality of Life in Elderly Patients with Advanced Cancer: A Physical Activity Intervention of the Multimodal Nutrition and Exercise Treatment for Advanced Cancer Program.

OBJECTIVE: Physical activity (PA) may improve the quality of life (QOL) of cancer survivors. However, the impact on patients with advanced cancer with high cachectic potential is unknown. We analyzed the feasibility of PA intervention using the multimodal program Nutrition and Exercise Treatment for Advanced Cancer (NEXTAC) and the impact on QOL in elderly patients with advanced cancer. METHODS: We recruited 30 patients aged ≥70 years who were scheduled to receive the first-line chemotherapy for newly diagnosed advanced pancreatic or non-small-cell lung cancer. The QOL was assessed using the European Organization for Research and Treatment of Cancer QOL Questionnaire version 3.0, while the PA was measured using a pedometer/accelerometer. Instructors counseled patients to increase daily activity in an 8-week educational intervention. We assessed patient attendance, compliance, and intervention efficacy. RESULTS: The median patients' age was 75 years (range, 70-84 years). Twelve patients (40%) were cachectic at baseline. Twenty-eight (93%) patients attended all sessions. Six (21%) and 15 (52%) patients increased their indoor and outdoor activity, respectively. There were significant differences in measured PA, global QOL, and role and emotional functioning between the patients who increased outdoor activity and those who did not. CONCLUSIONS: The PA intervention of the NEXTAC program was feasible as the elderly patients with advanced cancer in this study were highly compliant. The majority of patients demonstrated behavioral changes that were associated with the improvement in global QOL. We conduct a randomized phase II study to measure the impact of the NEXTAC program on QOL and functional prognosis.

Emphysematous pyelonephritis successfully treated by early intervention using a renoureteral catheter.

A 49-year-old woman with poorly controlled type 2 diabetes mellitus was admitted to hospital complaining of fever, vomiting, and lower abdominal pain. Laboratory investigation revealed leukocytopenia, high blood sugar, and pyuria. Pyelonephritis was then diagnosed. Escherichia coli was isolated from blood and urinary cultures. In spite of antimicrobial therapy, the patient's condition deteriorated. A computed tomography scan of the abdomen on the second day of hospitalization revealed the presence of air in the collecting system of the left kidney. Emphysematous pyelonephritis was diagnosed, and a renoureteral catheter was promptly inserted via the left ureter into the affected pelvis of the left kidney. Imipenem, cefotiam, and levofloxacin were administered during the clinical course. This early intervention and the appropriate antimicrobial therapy were effective in resolving the infection. Urinary tract infections should be carefully managed in patients with poorly controlled diabetes mellitus.