Effect of Eicosapentaenoic Acid/Docosahexaenoic Acid on Coronary High-Intensity Plaques Detected Using Noncontrast T1-weighted Imaging: The AQUAMARINE EPA/DHA Randomized Study.

AIM: Omega-3 fatty acids have emerged as a new option for controlling the residual risk for coronary artery disease (CAD) in the statin era. Eicosapentaenoic acid (EPA) is associated with reduced CAD risk in the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention trial, whereas the Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia trial that used the combination EPA/docosahexaenoic acid (DHA) has failed to derive any clinical benefit. These contradictory results raise important questions about whether investigating the antiatherosclerotic effect of omega-3 fatty acids could help to understand their significance for CAD-risk reduction. METHODS: The Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technic EPA/DHA study is a single-center, triple-arm, randomized, controlled, open-label trial used to investigate the effect of EPA/DHA on high-risk coronary plaques after 12 months of treatment, detected using cardiac magnetic resonance (CMR) in patients with CAD receiving statin therapy. Eligible patients were randomly assigned to no-treatment, 2-g/day, and 4-g/day EPA/DHA groups. The primary endpoint was the change in the plaque-to-myocardium signal intensity ratio (PMR) of coronary high-intensity plaques detected by CMR. Coronary plaque assessment using computed tomography angiography (CTA) was also investigated. RESULTS: Overall, 84 patients (mean age: 68.2 years, male: 85%) who achieved low-density lipoprotein cholesterol levels of ＜100 mg/dL were enrolled. The PMR was reduced in each group over 12 months. There were no significant differences in PMR changes among the three groups in the primary analysis or analysis including total lesions. The changes in CTA parameters, including indexes for detecting high-risk features, also did not differ. CONCLUSION: The EPA/DHA therapy of 2 or 4 g/day did not significantly improve the high-risk features of coronary atherosclerotic plaques evaluated using CMR under statin therapy.

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 .

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.

Risk factors for local recurrence after lobectomy and lymph node dissection in patients with non-small cell lung cancer: Implications for adjuvant therapy.

OBJECTIVES: The objective of this study was to investigate clinicopathological risk factors for local recurrence in patients who underwent either complete resection with lobectomy or more extensive resection with hilar and mediastinal lymph node dissection for non-small cell lung cancer (NSCLC). The role of adjuvant therapy was also explored. MATERIALS AND METHODS: We reviewed the records of 1012 consecutive stage I-III NSCLC patients who underwent complete resection. The median follow-up time was 59 months. The risk factors for local recurrence were investigated by multivariate analysis using Cox's proportional hazards regression model. RESULTS: Local recurrence was identified in 9.4% of the patients. The most significant risk factor for local recurrence was lymph node metastasis (N1: hazard ratio [HR]=2.27, p=0.009; N2: HR=6.85, p<0.0001). For the subgroup of patients with lymph node metastasis (n=289), the independent risk factors for local recurrence were N2 disease with N1 metastasis (N2 with N1; HR=3.46, p<0.0001) and non-receipt of adjuvant platinum-based chemotherapy (HR=1.91, p=0.018). The 5-year freedom from local recurrence rates were 96.1%, 84.1%, 85.0%, and 53.5% for N0, N1, skip N2, and N2 with N1 stages (p<0.0001). CONCLUSION: Local recurrence is significantly associated with poor overall survival. Therefore, local control is essential for radical cure of NSCLC. N2 with N1 status was the primary risk factor for local recurrence, while adjuvant chemotherapy improved local control. These data have important implications for postoperative radiotherapy and highlight the need to devise more effective eligibility criteria for this modality in patients with lymph node metastasis.