A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer.
ABSTRACT: BACKGROUND:Cancer cachexia is a syndrome of weight loss (including muscle and fat), anorexia, and decreased physical function. It has been suggested that the optimal treatment for cachexia should be a multimodal intervention. The primary aim of this study was to examine the feasibility and safety of a multimodal intervention (n-3 polyunsaturated fatty acid nutritional supplements, exercise, and anti-inflammatory medication: celecoxib) for cancer cachexia in patients with incurable lung or pancreatic cancer, undergoing chemotherapy. METHODS:Patients receiving two cycles of standard chemotherapy were randomized to either the multimodal cachexia intervention or standard care. Primary outcome measures were feasibility assessed by recruitment, attrition, and compliance with intervention (>50% of components in >50% of patients). Key secondary outcomes were change in weight, muscle mass, physical activity, safety, and survival. RESULTS:Three hundred and ninety-nine were screened resulting in 46 patients recruited (11.5%). Twenty five patients were randomized to the treatment and 21 as controls. Forty-one completed the study (attrition rate 11%). Compliance to the individual components of the intervention was 76% for celecoxib, 60% for exercise, and 48% for nutritional supplements. As expected from the sample size, there was no statistically significant effect on physical activity or muscle mass. There were no intervention-related Serious Adverse Events and survival was similar between the groups. CONCLUSIONS:A multimodal cachexia intervention is feasible and safe in patients with incurable lung or pancreatic cancer; however, compliance to nutritional supplements was suboptimal. A phase III study is now underway to assess fully the effect of the intervention.
Project description: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 .
Project description: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.
Project description:Cancer cachexia has impact on patients and their family members. Patients experience loss of weight often accompanied by anorexia and other debilitating symptoms that have clinical impact and impact everyday life. The importance of understanding this impact lies in (1) the alleviation of cachexia-related suffering and (2) its implications for treating cachexia.Two decades of exploratory investigation of the manifestations, meaning and management of cancer cachexia reveal emotional and social impacts for both patients and their carers. Patients can describe change in appearance and loss of physical strength often accompanied by change in eating habits (amount, type and pattern of food intake). The psychosocial effects can include loss of independence, sense of failure, sense of helplessness, conflict with family members over food, social isolation and thoughts of death. They are effects that can distress. Conversely, weight loss, especially early in its course and for those who are obese, can be perceived as beneficial, which inhibits self-management of diet and physical activity.Models of the psychosocial effects of cancer cachexia have been developed, leading to, as yet unproven, propositions of how negative patient and family impacts can be addressed. This literature overlooks the potential importance of psychosocial intervention to emerging multimodal treatments for the multicausal syndrome. Psychosocial intervention in cachexia should be tested for potential to help people affected by cancer cachexia feel better but also for potential to make people better by aiding uptake and compliance with multimodal therapy.
Project description:Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer-dependent on the underlying type of cancer-and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.
Project description:Multiple sclerosis (MS) is an incurable degenerative disease that attacks the central nervous system. Roy Swank proposed a low saturated fat diet to treat MS around 1950 and showed delayed disease progression in his patients. However, there is insufficient evidence to recommend this diet for MS and default dietary recommendations are the Dietary Guidelines for Americans (DGA). This study assessed the nutritional adequacy of seven-day menus developed by Swank and their compliance with the DGA; menus were modeled for comparison with the DGA Healthy US-Style Eating Pattern (HEP) for males and females 31⁻50 years. Swank recommended dietary supplements corrected menu shortfalls in vitamins D, E, calcium, folate and iron but not dietary fiber, potassium and choline. Healthy Eating Index-2015 score for Swank menus (93.2/100) indicated good compliance with the DGA. Nutritional adequacy of the Swank modeled diet was similar to HEP for 17 vitamins and minerals (Mean Adequacy Ratios ≥94%) with similar shortfall nutrients except magnesium (HEP males) and dietary fiber (Swank males). Alternate Healthy Eating Index-2010 scores for Swank male (90/110) and female (88/110) model diets were similar to HEP. Swank menus have similar nutritional adequacy as HEP. Inclusion of foods high in dietary fiber, potassium and choline may be advised as well as selection of foods to reduce sodium below the Tolerable Upper Intake Level.
Project description:Cachexia is a disease that has been recognized since antiquity; however, research in this area has recently increased. Promising new agents, including anamorelin hydrochloride, have been tested in large randomized controlled studies, and multidrug as well as multimodal approaches have been proposed as having the potential to improve outcomes in patients with cancer cachexia. However, standard treatment remains elusive. This review summarizes the current literature on treatment of cancer-associated cachexia, showing that there are challenges associated with conducting clinical trials in such patients. First, poor recruitment, retention, and compliance among cachectic patients cause research delays. Second, the lack of consensus regarding clinically meaningful endpoints impedes standardization of study designs and results. Further consideration is needed to identify the most suitable study design and endpoints, which can lead to the development of pharmacological and nonpharmacological interventions that improve patients' prognosis and outcomes.
Project description:Multiple sclerosis is an autoimmune disease influenced by environmental factors.The feasibility of a multimodal intervention and its effect on perceived fatigue in patients with secondary progressive multiple sclerosis were assessed.This was a single-arm, open-label intervention study in an outpatient setting.A multimodal intervention including a modified paleolithic diet with supplements, stretching, strengthening exercises with electrical stimulation of trunk and lower limb muscles, meditation, and massage was used.Adherence to each component of the intervention was calculated using daily logs. Side-effects were assessed from a monthly questionnaire and blood analyses. Fatigue was assessed using the Fatigue Severity Scale (FSS). Data were collected at baseline and months 1, 2, 3, 6, 9, and 12.Ten (10) of 13 subjects who were enrolled in a 2-week run-in phase were eligible to continue in the 12-month main study. Of those 10 subjects, 8 completed the study and 6 subjects fully adhered to the study intervention for 12 months. Over a 12-month period, average adherence to diet exceeded 90% of days, and to exercise/muscle stimulation exceeded 75% of days. Nutritional supplements intake varied among and within subjects. Group daily average duration of meditation was 13.3 minutes and of massage was 7.2 minutes. No adverse side-effects were reported. Group average FSS scores decreased from 5.7 at baseline to 3.32 (p=0.0008) at 12 months.In this small, uncontrolled pilot study, there was a significant improvement in fatigue in those who completed the study. Given the small sample size and completer rate, further evaluation of this multimodal therapy is warranted.
Project description:Lung cancer continues to be a major worldwide health issue, with more than 50% of patients having incurable metastatic disease at diagnosis. Fortunately, the advanced lung cancer treatment landscape is changing rapidly as a result of the positive impact of effective inhibitors of tumor driver mutations, and the more recent discovery that immune modulation with anti-PD-1/PD-L1 monoclonal antibodies results in tumor regression and prolonged survival. While a relatively small subset of lung cancer patients are candidates for inhibitors of driver mutations, the majority of advanced lung cancer patients are candidates for an immunotherapy regimen. Many of these patients have cachexia, which is associated with increased cancer therapy toxicity and possibly reduced responsiveness to immunotherapy. Two ongoing cachexia trials, one testing a ghrelin analogue and the other testing a multimodal strategy, have endpoints which assess clinical benefit-weight gain and relief of anorexia/cachexia symptoms. Provided that the trial objectives are achieved, these treatment strategies will provide a way to relieve suffering and distress for cachectic cancer patients. While awaiting the results of these trials, it would be reasonable to consider designing studies testing cachexia treatments combined with first-line immunotherapy and chemotherapy-immunotherapy in stage IV lung cancer patients, with enhanced overall survival being one of the endpoints.
Project description:Over the last decade, we have gained new insight into the pathophysiology of cachexia associated with pancreatic cancer. Unfortunately, its treatment is complex and remains a challenge. Pancreatic cancer cachexia is a multifactorial syndrome characterized by uncompensated adipose tissue and skeletal muscle loss in the setting of anorexia that leads to progressive functional impairment. This paper will review the current concepts of pancreatic cancer cachexia, its assessment and pathophysiology as well as current and future treatments. The successful management of pancreatic cancer cachexia will likely require a multimodal approach that includes nutritional support and combination pharmaceutical interventions.
Project description:Advanced cancer patients with disease progression develop cachexia. Nevertheless, cancer patients at nutritional risk have shown improved body weight and quality of life with oral nutritional supplements.This was a randomized controlled trial in adult female cancer patients (n = 63) attending palliative clinics, with symptoms of cachexia. Eligible patients were randomly distributed into control (n = 33) and intervention (n = 30) groups. Both groups were provided with nutritional and physical activity counseling, but the intervention group received an additional 100 g of Improved Atta (IAtta) for 6 months daily consumption. This study was designed to assess the efficacy of IAtta (with counseling) in enhancing the health status of cachexic patients. Anthropometric measurements, dietary intake, physical activity level and quality of life parameters were assessed at baseline, after 3 months, and at the end of 6 months.Patients in the control group (n = 15) had significantly decreased body weight ( P = .003), mid-upper-arm circumference ( P = .002), and body fat ( P = .002) by the end of intervention. A trend of body weight gain in the intervention group (n = 17; P = .08) and significant increase of body fat ( P = .002) was observed; moreover, patients reported a significant improvement in fatigue ( P = .002) and appetite scores ( P = .006) under quality-of-life domains at the end of intervention.Embedding a nutrition-sensitive intervention ( IAtta ) within Indian palliative care therapy may improve quality of life and stabilize body weight in cancer cachexia patients.