Nutrition therapy with high intensity interval training to improve prostate cancer-related fatigue in men on androgen deprivation therapy: a study protocol

Fatigue will be measured using The Functional Assessment of Cancer Therapy: Fatigue (FACT-F) questionnaire, which reports weekly fatigue on a scale of 0–52, with higher values indicating less fatigue [45]. The FACT-F has shown good reliability and validity (Cronbach’s α: 0.93-0.94) for predicting clinically significant treatment outcomes of CRF [46].

The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 is a 30 item cancer-specific instrument including the following domains; physical, role, emotional, social, and cognitive, global quality of life, fatigue, pain, and emesis. The EORTC QLQ-C30 has shown a high reliability (Cronbach’s α; 0.63-.80) in cancer patients [47].

The EORTC QLQ–PR25 is a 25 question prostate cancer-specific instrument including domains; urinary, bowel, use of incontinence aids, treatment-related symptoms, sexual activity and sexual function [48]. The EORTC QLQ – PR25 questionnaire has shown good internal reliability (Cronbach’s α; 0.70-0.86) for prostate specific treatment-related side effects [49].

The Medical Outcomes Study 36-Item Short-Form 36 Health Survey (SF-36) is scored by eight scales encompassing physical and mental measures [50]. The SF-36 questionnaire has widely been used to measure general health and well-being, with good construct validity (Cronbach’s α; > 0.85) in cancer patients [51].

Height, body mass, and waist circumferences will be measured according to the International Society for the Advancement of Kinathropometry (ISAK) procedures [52].

Body composition (fat mass, lean mass, body fat percentage and bone mineral density) will be assessed using dual energy X-ray absorptiometry (DXA; Hologic Discovery A, Waltham, MA, USA).

Isometric strength of dominate and non-dominate handgrip will be assessed using a spring-loaded grip dynamometer (TTM, Tokyo, Japan) to estimate physical performance [53], and muscular strength [54]. Participants will perform the test three times on each hand with the best result used for analysis. Muscular strength of the chest and legs will be measured using the one repetition maximum (1RM) chest and leg press methods, respectively [55]. The sit to stand test will be used to assess functional leg power [12]. Participants will perform the test three times with the best result used for analysis.

The six-meter walk test will involve participants walking a marked 10-m distance as quickly as safely possible, with performance timed over the middle 6-m distance to minimize the influence of acceleration and deceleration [12]. The 400-m walk test will be used to estimate exercise capacity [12]; participants will be required to walk 10 laps out and back over a 20-m course (400 m total) as fast as safely possible.

Cardiorespiratory fitness will be assessed using a V̇O_2peak test. The test will involve a modified ramp protocol described by Wasserman et al [56] on a cycle ergometer. Participants will begin with 3 min of rest for respiratory normalization, followed by 4 min of warm-up at a resistance of 50 Watt. The electrical resistance provided by the cycle ergometer increases incrementally by 20-30 W.min^-1. Participants will cycle at a cadence between 60 and 70 revolutions per minute throughout the test. Heart rate will be continuously recorded throughout the exercise using a heart rate monitor (Polar FT1; Polar, Kempele, Finland) and blood pressure (Durashock Sphygmomanometer; Welch Allyn, New York, USA) will be recorded every 2 min throughout the test. At the conclusion of each minute participants will indicate their rating of perceived exertion (RPE) on the Borg 6-20 scale [57]. The test will be terminated when the participant reaches volitional fatigue or at the discretion of the researchers with consideration for exercise testing termination criteria as outlined by the American Association of Cardiovascular and Pulmonary Rehabilitation [58]. The gas analyzers and ventilometer will be calibrated prior to and verified after each test. Sampled expired air will be measured every 15 s using a turbine ventilometer (Morgan, Model 096, Kent, England). The ramp V̇O_2peak protocol has good validity in comparison to the standard Bruce protocol [59]. V̇O_2peak will be recorded as the highest V̇O₂ reading averaged over two consecutive readings.

A trained phlebotomist will extract, treat and subsequently store the blood at approximately -80°C until later analysis. Analysis of blood samples through commercial ELISA kits (Thermo Fisher Scientific Australia Pty Ltd., Victoria, Australia; Randox Laboratories Ltd., West Virginia, USA; R&D Systems Inc., Minneapolis, USA) will be used for PSA, IGF-1, IGF-2, IGFBP3, IL-6, IL-8, Hepcidin, total cholesterol, and triglycerides analysis.

Participants will complete the Wollongong Dietary Inventory [60] (a comprehensive dietary history of intake over the past month) with cross-checking quantification from an Accredited Practising Dietitian. Narrative approaches to diet histories have been shown to provide good reproducibility and reliability compared to food records [61]. Food models and pictures of food portions (Great Ideas in Nutrition, Coolangatta, Australia) will be utilized to improve the accuracy of food intake estimates [62].

The DASS is a 42-item self-report instrument design to measure the three related negative emotional states of depression, anxiety, and stress [63], and has been validated for measuring emotional states of depression (Cronbach’s α: 0.94), anxiety (Cronbach’s α: 0.88) and stress (Cronbach’s α: 0.93) in clinical populations [64].

The ISI questions relate to subjective qualities of the respondents sleep, including satisfaction with sleep patterns, the degree to which insomnia interferes with daily functioning, and how the respondent feels their insomnia is noticeable to others [65]. The ISI has shown excellent internal consistency (Cronbach’s α: 0.90) for detecting symptoms of insomnia.

The physical activity enjoyment scale (PACES) will be used to assess participant enjoyment of the high intensity interval exercise PACES consists of 17 subscales that each relate to an aspect of enjoyment; along a 7-point continuum for each subscale, participants are asked to provide a rating to reflect their agreement with one of two bi-polar statements (e.g. ‘I enjoy it’ – ‘I hate it’) [66]. The PACES questionnaire has shown high internal consistency (Cronbach’s α: 0.90) in measures of exercise enjoyment [67].

The Godin leisure-time physical activity questionnaire requires participants to recall during a typical 7-day week the frequency and duration of exercise completed at three separate intensities: mild, moderate, and strenuous intensity [68]. The Godin leisure-time physical activity questionnaire has shown high agreement and validation (agreement: 70.8%) with minutes spent physically active, in comparison to an accelerometer in breast cancer survivors [69].

Participants will be asked to maintain their current level of physical activity outside of the testing sessions for the duration of the study. Physical activity will be objectively assessed using the Actigraph GT3X+ accelerometer (Actigraph, Pensacola, Florida), a small, waist-worn, non-invasive device. Few studies have been published on the validity of the GT3X+ version of the Actigraph accelerometer specifically, however previous versions of the Actigraph accelerometer (CSA and GT1M) have demonstrated waist-worn validity in treadmill walking and running compared with indirect calorimetry (r = 0.56, p < 0.001 and r = 0.53, p < 0.05, respectively) in adults [70, 71].

Detailed diet histories will be conducted at baseline week 8, 12 and 20 using the Wollongong Dietary Inventory [60], and 24 h diet recalls every two weeks during the intervention. Each consult will take approximately 30-45 min and involves an Accredited Practising Dietitian asking detailed questions about the foods consumed and the amount and frequency of consumption. The 20-week diet emphasizes a total energy intake decrement using the Harris-Benedict predicted energy requirements [72]; with a dietary composition of 45-65% carbohydrate, 20-35% fat, saturated fat <10% total energy intake, and 15-25% protein sources. Dietary advice will be tailored according to current body composition classification as ‘normal, overweight or obese stage I’ (see Fig. 2). A dietary energy reduction of 2000-4000 kJ/day will be emphasized at baseline consultation if body composition and diet intake are classified average or poor according to Fig. 2: Nutrition therapy schematic representation. The diet intervention will encompass a Mediterranean-style diet containing cruciferous vegetables (broccoli, bok choy, cauliflower) [73], tomato and tomato-paste containing products (lycopene) [74, 75], fruits, calcium and vitamin D containing foods, polyunsaturated, monounsaturated, omega 3 and 6 fatty acids (<10–15% total energy intake) [76], and a reduced consumption of red meat (<2 a week) [77, 78]; as seen in Table 2: Nutrition recommendations. Each individual nutritional consultation, will aim to make gradual changes to the participants’ diets to best achieve a modified Mediterranean-style dietary pattern. Standard dietetics practice will be used to assess and providing guidance on managing the nutritional impact symptoms from treatment (including broader intolerances/allergies).

Each participant in the intervention group will be provided with a nutrition pamphlet for supportive education during the study to represent standard dietetic practice. The nutrition pamphlet will be provided at the first dietetic consult and is designed to facilitate the dietetic consultation to help maintain a Mediterranean-style diet pattern. The pamphlet consists of background information about nutrition requirements, optimal nutrition during prostate cancer based on current evidence (kilojoule/cal, fatty acids, carbohydrate, meats and protein, fruits and vegetables, cruciferous vegetables, lycopene, soy isoflavones, vitamin C and calcium, alcohol and discretionary foods) and exercise during prostate cancer treatment. The pamphlet further consists of Decision Balance Tools to help change dietary patterns if needed throughout the dietetic consults by identifying possible barriers to adopting the nutrition therapy. These form part of standard dietetics practice involving motivational interviewing.

Baseline body composition scans (DXA) will classify participants as normal, overweight, or obese state I, according to age specific normative Z values for percentage of body mass index and fat mass [79]. The current diet will be quantified into food groups, total energy intake, and saturated fat intake. From this the diet will be classified as ‘generally healthy’, ‘average’ or ‘poor’ compared to the Australian Dietary Guidelines [80] (as seen in Fig. 2: Nutrition therapy schematic representation). To improve adherence, the nutrition therapy will not be prescriptive, and instead utilize individualized food-based goals with the aim to progressively increase the intake of plant-based foods over the duration of the intervention to meet a modified Mediterranean-style diet pattern.

From weeks 12–20 participants will be required to visit The University of Queensland’s School of Human Movement and Nutrition Sciences three times per week to complete high intensity interval training sessions. Prior to exercising, participants’ heart rate and blood pressure will be measured for contraindications to commence exercising as outlined by the American College of Sports Medicine [81]. The high intensity exercise sessions will commence with 10 min of warm up at 50–70% HR_peak before completing 4 x 4 min bouts of cycling at 85–95% HR_peak. Each 4 min interval will be interspersed with a 3 min period of active recovery at 50–70% HR_peak, totaling 38 min for the session. The high intensity exercise sessions will be conducted on an air- and magnetically-braked cycle ergometer (Wattbike Ltd., Nottingham, England). Participants will continue to receive the same dietetic intervention outlined above from weeks 12–20.

Participants randomized to usual care will continue their usual medical care during this period. Participants in the usual care group will be monitored for 20 weeks and perform identical primary and secondary outcome measures at the same time points as outlined above for the intervention group.