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Mediterranean Style Dietary Pattern with High Intensity Interval Training in Men with Prostate Cancer Treated with Androgen Deprivation Therapy: A Pilot Randomised Control Trial.
Baguley, BJ, Adlard, K, Jenkins, D, Wright, ORL, Skinner, TL
International journal of environmental research and public health. 2022;19(9)
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The use of androgen deprivation therapy (ADT) has coincided with improvements in disease control and improved overall survivorship in many men treated for prostate cancer. Exercise and nutrition interventions during and/or after ADT are strongly recommended to mitigate or improve body composition and reduce cardiometabolic side effects. The aim of this study was to examine the combined effects of a Mediterranean diet (MED-diet) and high intensity interval training (HIIT) on cardiorespiratory fitness, body composition and quality of life, compared to usual care, in men with prostate cancer treated with ADT. This study is a two-arm randomised controlled trial. Participants (n = 23) were randomly allocated to either an intervention or usual care group in a 1:1 ratio. Results show that for men with prostate cancer undergoing ADT, a MED-diet with HIIT compared to usual care at 20 weeks (i) significantly improved cardiorespiratory fitness relative; (ii) reduced body weight; (iii) maintained lean body mass despite achieving weight loss; (iv) significantly improved vitality and mental health composite, and clinical improvements were seen in prostate-cancer specific quality of life and cancer-related fatigue. Authors conclude that future larger-scale trials examining the MED-diet with HIIT on cardiorespiratory fitness, body composition and quality of life would help to extend the findings of their study.
Abstract
Background: Androgen deprivation therapy (ADT) in prostate cancer has been shown to deteriorate body composition (reduced lean mass and increased body and fat mass) and increase the risk of cardiovascular morbidity. The Mediterranean style dietary pattern (MED-diet) and high intensity interval training (HIIT) may synergistically alleviate these side effects and improve quality of life in men treated with ADT. Methods: Twenty-three men (65.9 ± 7.8 years; body mass index: 29.6 ± 2.7 kg/m2; ADT duration: 33.8 ± 35.6 months) receiving ADT for ≥3 months were randomly assigned (1:1) to 20 weeks of usual care or the MED-diet (10 nutrition consults) with HIIT (4 × 4 min 85−95% heart rate peak, 3× week, starting at 12 weeks). Results: The MED-diet with HIIT significantly improved cardiorespiratory fitness (+4.9 mL·kg−1·min, p < 0.001), and body mass (−3.3 kg, p < 0.001) compared to the usual care group at 20 weeks. Clinically meaningful (≥3 points) improvements were seen in quality of life and cancer-related fatigue after 20 weeks. Conclusions: The MED-diet with HIIT increased cardiorespiratory fitness and reduced body weight in men with prostate cancer treated with ADT. Larger trials determining whether the MED-diet with HIIT translates to cardiovascular benefits are warranted.
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A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.
Basak, SK, Bera, A, Yoon, AJ, Morselli, M, Jeong, C, Tosevska, A, Dong, TS, Eklund, M, Russ, E, Nasser, H, et al
Cancer. 2020;126(8):1668-1682
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APG-157 is a botanical drug containing multiple polyphenols that delivers the active components to oromucosal tissues near the tumour target. APG-157 slowly disintegrates in the oral cavity over 15 to 20 minutes to release the drug substance. The drug substance is a precise, rational combination of multiple molecules derived from Curcuma longa wherein curcumin is the principal component. The main aim of this study was to determine the pharmacokinetics and safety of the orally delivered pastille (APG-157) when used by normal subjects and patients with cancer. This study is a randomised, double-blind, placebo-controlled trial. A total of 32 subjects were enrolled, and 25 completed the study (13 normal individuals and 12 patients with oral cancer). Results demonstrated that transoral APG-157 treatment leads to systemic absorption of curcumin and its analogs. There was a statistically significant concentration reduction in inflammatory cytokines and Bacteroides species noted in the salivary cells. Pre-treatment and post-treatment tumour samples from patients with cancer demonstrated T-cell recruitment to the tumour microenvironment. Authors conclude that APG-157 is absorbed well, reduces inflammation, and attracts T-cells to the tumour thus, it can be potentially used in combination with immunotherapy drugs. Furthermore, a long-term evaluation of immune checkpoint blockade with and without APG-157 could provide a clear understanding of the usefulness of APG-157 as either an adjuvant or neoadjuvant therapeutic agent for patients with advanced or recurrent head and neck cancer.
Abstract
BACKGROUND Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. METHODS A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. RESULTS Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment. CONCLUSIONS The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy. LAY SUMMARY Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.
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Exercise Preserves Physical Function in Prostate Cancer Patients with Bone Metastases.
Galvão, DA, Taaffe, DR, Spry, N, Cormie, P, Joseph, D, Chambers, SK, Chee, R, Peddle-McIntyre, CJ, Hart, NH, Baumann, FT, et al
Medicine and science in sports and exercise. 2018;50(3):393-399
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Existing research indicates cancer patients with bone metastases should not participate in exercise due to potential risks to the skeletal system. However, current oncology guidelines suggest that all cancer patients should avoid inactivity, including those with bone metastases. The purpose of this study is to determine the safety and efficacy of exercise among 57 prostate cancer patients with bone metastases. Participants were randomised to either participate in exercise or receive usual care for three months. Exercise consisted of supervised aerobic activity, resistance training and stretching three days a week. Overall health status and physical function was measured by self-reported questionnaire. This study found self-reported physical functioning and lower muscle strength was improved significantly in the exercise group. There were no difference in bone pain between groups, and no adverse events occurred. Based on these results, the authors conclude exercise is safe and can help improve physical functioning among prostate cancer patients with bone metastasis.
Abstract
PURPOSE The presence of bone metastases has excluded participation of cancer patients in exercise interventions and is a relative contraindication to supervised exercise in the community setting because of concerns of fragility fracture. We examined the efficacy and safety of a modular multimodal exercise program in prostate cancer patients with bone metastases. METHODS Between 2012 and 2015, 57 prostate cancer patients (70.0 ± 8.4 yr; body mass index, 28.7 ± 4.0 kg·m) with bone metastases (pelvis, 75.4%; femur, 40.4%; rib/thoracic spine, 66.7%; lumbar spine, 43.9%; humerus, 24.6%; other sites, 70.2%) were randomized to multimodal supervised aerobic, resistance, and flexibility exercises undertaken thrice weekly (EX; n = 28) or usual care (CON; n = 29) for 3 months. Physical function subscale of the Medical Outcomes Study Short-Form 36 was the primary end point as an indicator of patient-rated physical functioning. Secondary end points included objective measures of physical function, lower body muscle strength, body composition, and fatigue. Safety was assessed by recording the incidence and severity of any adverse events, skeletal complications, and bone pain throughout the intervention. RESULTS There was a significant difference between groups for self-reported physical functioning (3.2 points; 95% confidence interval, 0.4-6.0 points; P = 0.028) and lower body muscle strength (6.6 kg; 95% confidence interval, 0.6-12.7; P = 0.033) at 3 months favoring EX. However, there was no difference between groups for lean mass (P = 0.584), fat mass (P = 0.598), or fatigue (P = 0.964). There were no exercise-related adverse events or skeletal fractures and no differences in bone pain between EX and CON (P = 0.507). CONCLUSIONS Multimodal modular exercise in prostate cancer patients with bone metastases led to self-reported improvements in physical function and objectively measured lower body muscle strength with no skeletal complications or increased bone pain. TRIAL REGISTRATION ACTRN12611001158954.
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Feasibility outcomes of a presurgical randomized controlled trial exploring the impact of caloric restriction and increased physical activity versus a wait-list control on tumor characteristics and circulating biomarkers in men electing prostatectomy for prostate cancer.
Demark-Wahnefried, W, Nix, JW, Hunter, GR, Rais-Bahrami, S, Desmond, RA, Chacko, B, Morrow, CD, Azrad, M, Frugé, AD, Tsuruta, Y, et al
BMC cancer. 2016;16:61
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There is a strong body of evidence associating obesity and increased risk for more aggressive and progressive cancer. This paper aims to assess the feasibility of a presurgical diet and exercise weight loss intervention in men with newly-diagnosed prostate cancer who elected for prostatectomy. It also aims to explore the intervention’s effects on tumour proliferation rates and other biomarkers. The 3-weeks randomised controlled study included 40 overweight or obese men newly-diagnosed with prostate cancer. Participants in experimental arm were assigned to a healthy energy-restricted diet versus wait-list control arm. All feasibility endpoints were achieved with accrual completed within 2 years, retention of 85%, adherence of 95% and no adverse events. Biologic outcomes were not included in this paper, as biological testing was still ongoing. Authors concluded that this study’s methods and data on feasibility could provide useful framework for the design of future trials. They also highlighted the importance of presurgical trials as a feasible and safe means to assess the impacts of diet and exercise on tumour tissue.
Abstract
BACKGROUND Obesity is associated with tumor aggressiveness and disease-specific mortality for more than 15 defined malignancies, including prostate cancer. Preclinical studies suggest that weight loss from caloric restriction and increased physical activity may suppress hormonal, energy-sensing, and inflammatory factors that drive neoplastic progression; however, exact mechanisms are yet to be determined, and experiments in humans are limited. METHODS We conducted a randomized controlled trial among 40 overweight or obese, newly-diagnosed prostate cancer patients who elected prostatectomy to explore feasibility of a presurgical weight loss intervention that promoted a weight loss of roughly one kg. week(-1) via caloric restriction and physical activity, as well as to assess effects on tumor biology and circulating biomarkers. Measures of feasibility (accrual, retention, adherence, and safety) were primary endpoints. Exploratory aims were directed at the intervention's effect on tumor proliferation (Ki-67) and other tumor markers (activated caspase-3, insulin and androgen receptors, VEGF, TNFβ, NFκB, and 4E-BP1), circulating biomarkers (PSA, insulin, glucose, VEGF, TNFβ, leptin, SHBG, and testosterone), lymphocytic gene expression of corresponding factors and cellular bioenergetics in neutrophils, and effects on the gut microbiome. Consenting patients were randomized in a 1:1 ratio to either: 1) weight loss via a healthful, guidelines-based diet and exercise regimen; or 2) a wait-list control. While biological testing is currently ongoing, this paper details our methods and feasibility outcomes. RESULTS The accrual target was met after screening 101 cases (enrollment rate: 39.6%). Other outcomes included a retention rate of 85%, excellent adherence (95%), and no serious reported adverse events. No significant differences by age, race, or weight status were noted between enrollees vs. non-enrollees. The most common reasons for non-participation were "too busy" (30%), medical exclusions (21%), and "distance" (16%). CONCLUSIONS Presurgical trials offer a means to study the impact of diet and exercise interventions directly on tumor tissue, and other host factors that are feasible and safe, though modifications are needed to conduct trials within an abbreviated period of time and via distance medicine-based approaches. Pre-surgical trials are critical to elucidate the impact of lifestyle interventions on specific mechanisms that mediate carcinogenesis and which can be used subsequently as therapeutic targets. TRIAL REGISTRATION NCT01886677.