Rosa Greasley BSc MSc(Res) PGCertDirector of studies: Dr Liam Bourke

Supervisors: Mr Derek Rosario, Prof Karen Collins

PresenterPresentation NotesThank you for giving up your valuable time for my RF2 today, I am looking forward to hearing your feedback. So I am just going to start with this little refresher on my planned programme of research.

Initial presentation, investigation and referral

Diagnosis, staging and treatment planning

Localised prostate cancer

Locally advanced prostate cancer

Advanced prostate cancer (metastatic)

Treatment: Watchful waiting, active surveillance, surgery,

radiation therapy or brachytherapy +/– ADT

Treatment: Androgen deprivation therapy (ADT)

Disease relapse: Castrate resistant prostate cancer

Treatments:

Second generation

antiandrogens

Bone therapies

Carbazitaxel

Docetaxel

Plus docetaxel

Death

Prog

ress

ion

PresenterPresentation NotesSo first I just want to give you a bit of an idea of the prostate cancer care pathway and introduce you to castrate resistant prostate cancer.

Treatments: It is important to note that at this point none of these treatments are curative and are essentially palliative. There are currently no supportive interventions for me nwith CRPC which is where I hope my lifestyle intervention could bridge a gap and an unmet clinical need. The 2 recent trials CHARRTED and STAMPEDE demonstarted a survival benefit with docetaxel being introduced earlier in the pathway which has significantly changed treatment paradigms. This has brought about a lot of uncertainty further down the treatment pathway too.

ADT is associated with significant adverse events including:• Cardiovascular disease and cardiovascular death• Diabetes• Fatigue • Renal disease• Bone fracture risk • Cognitive dysfunction • Depression • Hot flushes • Sexual dysfunction• Reduced lean body mass and increased body fat mass(1-12)

• NICE guidelines • Improvements in prostate cancer specific

outcomes (13)• Improved overall survival in men with

metastatic prostate cancer with increased lean body mass (14)

• Resistance and aerobic training in cancer populations has demonstrated an increase in chemotherapy completion rate (15)

• Preliminary data - Anti-tumour effects of a low carbohydrate and high protein diet (16-19)

• High protein diet and resistance exercise to improve outcomes in men with CRPC

PresenterPresentation NotesOffer men who are starting or having androgen deprivation therapy supervised resistance and aerobic exercise at least twice a week for 12 weeks to reduce fatigue and improve quality of life. [new 2014]

Multiple pre-clinical and clinical studies, including observational cohort studies, have demonstrated anti-tumour effects of a low carbohydrate and high protein diet [41-45]. In addition, a high fibre diet has been associated with chemoprotective effects, lowering the risk of colorectal cancer [46, 47].

Is a supportive intervention of a 16 week combined programme of exercise training,

dietary advice and supplementation feasible?

Hypothesis• A 16 week programme of resistance exercise,

dietary advice and supplementation in men with CRPC will be feasible.

PresenterPresentation NotesSo my final study is the feasibility RCT where I will recruit 50 men at a randomisation ratio of 1:1My hypothesis is...And secondary outcomes include, quality of life, physical function and lean body mass

• Population – Men with CRPC• Intervention – 16 week lifestyle intervention• Comparison – “Standard care”• Outcomes - Feasibility and safety

• Research sites- SHU, STH (Weston Park and Sheffield Hallamshire Urology Dept)

• 16 week programme of exercise involving up to three supervised exercise sessions a week

• Participants will perform 3-4 sets of 6-12 repetitions of 6 resistance exercises.

• Participants will be asked to undertake and log at least one independent 30 minute aerobic activity at home during this period.

PresenterPresentation NotesThe activity chosen will be based on that most convenient for the participant (such as walking or making use of community exercise facilities). In the record book participants will be asked to record the time of activity, duration and exercise intensity based on the Borg rating of perceived exertion scale, details of which will be provided in the booklet [40]. The participant logged activity will be documented when participants attend supervised exercise sessions and further encouraged to undertake aerobic exercise through goal setting and self-regulation.

• Short seminar in a small group format on healthy eating and an information booklet with dietary guidance and recipes.

• Dietary supplementation– Whey protein– Creatine

PresenterPresentation NotesDietary advice will encourage participants to adopt a diet rich in nutrient dense whole foods, fruit and vegetables and discourage processed foods and those high in refined carbohydrates and saturated fats. Participants will also be asked to limit alcohol intake. Recipes provided will encourage high protein, moderate fat, high fibre and low carbohydrate meals.

: To promote muscle protein synthesis, participants will be required to increase protein consumption via whey protein supplementation provided. Whey protein is rapidly digested and has a high leucine content which appears more efficient at muscle protein synthesis than other protein alternatives (e.g. soya protein) post-resistance exercise [48]. Participants will be provided with whey protein post-supervised exercise sessions and to take home where they will be advised to consume with 300-500ml of fat-free milk or water [49]. The recommended dosage of protein will be bodyweight (kg-1)* 1.2 g/day as previously described [50].

Studies have shown that a combination of whey protein and creatine promote increases in LBM [50]. The intervention group in our trial will be asked to take 0.25 g·kg-1 of LBM a day of creatine during the acute loading phase (the first 5 days of creatine supplementation) and thereafter a maintenance dose of 5 grams per day. Adverse effects associated with doses are likely to be minimal. In older adults, six months of creatine supplementation at 5 grams per day reported only one instance of gastrointestinal distress (stomach cramps), a ratio of 1 in 21, or a 4.8% liklihood.[51] The study authors noted these cramps did not result in the patient withdrawing from the study. To add further reassurance, in advanced colo-rectal cancer patients undergoing chemotherapy, a double blind randomised trial reported no significant differences in nausea, vomiting, pain, dyspnoea, insomnia, appetite loss, constipation or diarrhoea after 8 weeks of creatine supplementation (20g per day loading phase [first seven days] and then 5g per day for the following 7 weeks.[17]

• The primary outcome will be the feasibility measures:

• Recruitment rate• Adherence and attrition• Loss to follow-up• Adverse events/serious adverse events rate

PresenterPresentation NotesFeasibility: attrition, rate of recruitment, adherence etc

• Dual-energy X-ray absorptiometry (DEXA scan):– Appendicular lean body mass (kg)– Fat mass (kg)– Bone mineral

density.

• Physical function • QoL

(21)

Task Oct-16 Nov-16 Dec-16 Jan-17 Feb-17 Mar-17 Apr-17 May-17 Jun-17 Jul-17 Aug-17 Sep-17

COMRADEEthics application and approvalRecruitmentInterventionAnalysisAdditional training

Oct-17 Nov-17 Dec-17 Jan-18 Feb-18 Mar-18 Apr-18 May-18 Jun-18 Jul-18 Aug-18 Sep-18RecruitmentInterventionAnalysisFollow up interviewsWrite up for publication

Date (month-year)

PresenterPresentation NotesSo this is my second year, and I hope to start my recruitment process by december/ january of next year with my first participants starting the trial by February of next year.

Sheet1

Task Date (month-year)

Oct-16Nov-16Dec-16Jan-17Feb-17Mar-17Apr-17May-17Jun-17Jul-17Aug-17Sep-17

COMRADE

Ethics application and approval

Recruitment

Intervention

Analysis

Additional training

Oct-17Nov-17Dec-17Jan-18Feb-18Mar-18Apr-18May-18Jun-18Jul-18Aug-18Sep-18

Recruitment

Intervention

Analysis

Follow up interviews

Write up for publication

• 50 men in total (20)

• 1 man a week

• Identifying menin oncology and urologyclinics

0

10

20

30

40

50

60

Num

ber o

f par

ticip

ants

Month/Year

Target accrual

Cumulative accrual

PresenterPresentation NotesLancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract. 2004;10(2):307-12.

• An evaluation of a resistance exercise and dietary intervention in an advanced prostate cancer population and its associated changes to quality of life, physical function outcomes and lean body mass

PresenterPresentation NotesSo my contribution to knowledge is that this will be the first published evaluation of a resistance excercise...

Where currently there is an unmet clinical need for supportive interventions for men with CRPC.

• Supervisors: Dr Liam Bourke, Mr Derek Rosario, Prof Karen Collins

• Clinical advisor: Prof Janet Brown

• All those at STH who helped facilitate these projects.

PresenterPresentation NotesI would like to thank all of those who have contributed and help to facilitate these studies because without this would not be possible. The STAMINA team for all there help so far and continuing help for my future trial.Supervisor KCMed onc JB

email: r.greasley@shu.ac.uk

(1) Nguyen PL, Alibhai SMH, Basaria S, et al. Adverse Effects of Androgen Deprivation Therapy and Strategies to Mitigate Them. European Urology 2015;67:825-36.(2) Smith MR, Lee H, Fallon MA, Nathan DM. Adipocytokines, obesity, and insulin resistance during combined androgen blockade for prostate cancer. Urology 2008;71:318-22.(3) Smith MR, Lee H, Nathan DM. Insulin sensitivity during combined androgen blockade for prostate cancer. J Clin Endocrinol Metab 2006;91:1305-8.(4)Keating NL, O'Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst 2010;102:39-46.(5) Van Hemelrijck M, Garmo H, Holmberg L, et al. Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the Population-Based PCBaSe Sweden. J Clin Oncol 2010;28:3448-56.(6) O'Farrell S, Sandstrom K, Garmo H, et al. Risk of thromboembolic disease in men with prostate cancer undergoing androgen deprivation therapy. BJU Int 2016;118:391-8.(7) Fowler FJ, Jr., McNaughton Collins M, Walker Corkery E, Elliott DB, Barry MJ. The impact of androgen deprivation on quality of life after radical prostatectomy for prostate carcinoma. Cancer 2002;95:287-95.(8) Bourke L, Chico TJ, Albertsen PC, Hamdy FC, Rosario DJ. Cardiovascular risk in androgen suppression: underappreciated, under-researched and unresolved. Heart 2011;98:345-8.(9) Gandaglia G, Sun M, Hu JC, et al. Gonadotropin-releasing Hormone Agonists and Acute Kidney Injury in Patients with Prostate Cancer. Eur Urol 2014:66(6):1125-32.(10) Dacal K, Sereika SM, Greenspan SL. Quality of life in prostate cancer patients taking androgen deprivation therapy. J Am Geriatr Soc 2006;54:85-90.(11) Stone P, Hardy J, Huddart R, A'Hern R, Richards M. Fatigue in patients with prostate cancer receiving hormone therapy. Eur J Cancer 2000;36:1134-41.(12) Bourke L, Boorjian SA, Briganti A, et al. Survivorship and Improving Quality of Life in Men with Prostate Cancer. Eur Urol 68(3):374-83 2015.(13) Bourke L, Smith D, Steed L, Hooper R, Carter A, Catto J, et al. Exercise for Men with Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2015:69(4):693-703.(14)Wu W, Liu X, Chaftari P, Cruz Carreras MT, Gonzalez C, Viets-Upchurch J, et al. Association of body composition with outcome of docetaxel chemotherapy in metastatic prostate cancer: a retrospective review. PloS one. 2015;10:e0122047.(15) Courneya KS, Segal RJ, Mackey JR, et al. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007;25(28):4396-404. doi: 10.1200/JCO.2006.08.2024(16)Fung TT, Hu FB, Hankinson SE, Willett WC, Holmes MD. Low-carbohydrate diets, dietary approaches to stop hypertension-style diets, and the risk of postmenopausal breast cancer. American journal of epidemiology. 2011;174(6):652-60.(17)Fokidis HB, Yieng Chin M, Ho VW, Adomat HH, Soma KK, Fazli L, et al. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice. J Steroid Biochem Mol Biol. 2015;150:35-45.(18)Terry PD, Jain M, Miller AB, Howe GR, Rohan TE. Glycemic load, carbohydrate intake, and risk of colorectal cancer in women: a prospective cohort study. Journal of the National Cancer Institute. 2003;95(12):914-6.(19)Slattery ML, Benson J, Berry TD, Duncan D, Edwards SL, Caan BJ, et al. Dietary sugar and colon cancer. Cancer Epidemiology Biomarkers & Prevention. 1997;6(9):677-85.(20) Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract. 2004;10(2):307-12.(21) Image taken from: https://coconuts.co/hongkong/news/fitness-fad-fridays-analysing-body-fat-scary-precision-using-dexa-scan/

https://coconuts.co/hongkong/news/fitness-fad-fridays-analysing-body-fat-scary-precision-using-dexa-scan/

NIHR portfolio study COMRADE:�A Combined Programme of Exercise and Dietary Advice in Men with Castrate Resistant Prostate CancerSlide Number 2Slide Number 3Exercise, Diet and Prostate CancerResearch Question Feasibility RCT: COMRADESlide Number 7Study designSlide Number 9Slide Number 10Feasibility trial: primary outcomesSlide Number 12COMRADE GANTT Recruitment strategyContribution to knowledgeAcknowledgements Thank you for listeningReferences