Edith Cowan University Research Online ECU Publications Post 2013 2017 Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy Nicolas H. Hart Edith Cowan University Robert Newton Edith Cowan University Nigel Spry Edith Cowan University Dennis Taaffe Edith Cowan University Suzanne K. Chambers Edith Cowan University See next page for additional authors Follow this and additional works at: https://ro.ecu.edu.au/ecuworkspost2013 Part of the Medicine and Health Sciences Commons 10.1136/bmjopen-2016-014458 Hart, N. H., Newton, R. U., Spry, N. A., Taaffe, D. R., Chambers, S. K., Feeney, K. T., ... & Galvão, D. A. (2017). Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy. BMJ open, 7(5), e014458. Available here This Journal Article is posted at Research Online. https://ro.ecu.edu.au/ecuworkspost2013/2960 Authors Nicolas H. Hart, Robert Newton, Nigel Spry, Dennis Taaffe, Suzanne K. Chambers, Kynan Feeney, David Joseph, Andrew D. Redfern, Tom Ferguson, and Daniel A. Galvao This journal article is available at Research Online: https://ro.ecu.edu.au/ecuworkspost2013/2960 Downloaded from http://bmjopen.bmj.com/ on June 20, 2017 - Published by group.bmj.com Open Access Protocol Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy Nicolas H Hart,1 Robert U Newton,1 Nigel A Spry,1,2,3 Dennis R Taaffe,1 Suzanne K Chambers,1,4 Kynan T Feeney,1,5,6 David J Joseph,1,2,3 Andrew D Redfern,7,8 Tom Ferguson,7 Daniel A Galvão1 To cite: Hart NH, Newton RU, ABSTRACT Strengths and limitations of this study Spry NA, et al. Can exercise Introduction Exercise may positively alter tumour biology suppress tumour growth in through numerous modulatory and regulatory mechanisms advanced prostate cancer ► This is a novel, phase I randomised controlled trial in patients with sclerotic bone in response to a variety of modes and dosages, evidenced humans exploring the preliminary effects of targeted metastases? A randomised, in preclinical models to date. Specifically, localised and exercise on tumour morphology and circulating controlled study protocol systemic biochemical alterations produced during and metastatic tumour biomarkers using a sclerotic examining feasibility, safety following exercise may suppress tumour formation, skeletal metastases model in patients with prostate and efficacy. BMJ Open growth and distribution by virtue of altered epigenetics cancer. 2017;7:e014458. doi:10.1136/ and endocrine–paracrine activity. Given the impressive ► The study is principally aimed at establishing bmjopen-2016-014458 ability of targeted mechanical loading to interfere with feasibility and safety, and may lack statistical power ► Prepublication history and metastasis-driven tumour formation in human osteolytic or a suitable length of intervention to determine additional material are available. tumour cells, it is of equal interest to determine whether the efficacy of exercise on tumour biology and To view these files please visit a similar effect is observed in sclerotic tumour cells. The metastatic tumour biomarkers. the journal online (http:// dx. doi. study aims to (1) establish the feasibility and safety of a org/ 10. 1136/ bmjopen- 2016- combined modular multimodal exercise programme with 014458). spinal isometric training in advanced prostate cancer treat approach with multiple imputations, followed by a Received 26 September 2016 patients with sclerotic bone metastases and (2) examine secondary sensitivity analysis to ensure data robustness Revised 10 February 2017 whether targeted and supervised exercise can suppress Accepted 20 March 2017 sclerotic tumour growth and activity in spinal metastases using a complete cases approach. in humans. Ethics and dissemination Ethics approval was obtained Methods and analysis A single-blinded, two-armed, from the Human Research Ethics Committee (HREC) of randomised, controlled and explorative phase I clinical Edith Cowan University and the Sir Charles Gairdner and trial combining spinal isometric training with a modular Osborne Park Health Care Group. If proven to be feasible multimodal exercise programme in 40 men with advanced and safe, this study will form the basis of future phase prostate cancer and stable sclerotic spinal metastases. II and III trials in human patients with advanced cancer. Participants will be randomly assigned to (1) the exercise To reach a maximum number of clinicians, practitioners, intervention or (2) usual medical care. The intervention patients and scientists, outcomes will be disseminated arm will receive a 3-month, supervised and individually through national and international clinical, conference tailored modular multimodal exercise programme with and patient presentations, as well as publication in high- spinal isometric training. Primary endpoints (feasibility impact, peer-reviewed academic journals. and safety) and secondary endpoints (tumour morphology; Trial registration number ACTRN 12616000179437. biomarker activity; anthropometry; musculoskeletal health; adiposity; physical function; quality of life; anxiety; INTRODUCTION distress; fatigue; insomnia; physical activity levels) will be measured at baseline and following the intervention. Bone is the most common location for meta- For numbered affiliations see Statistical analyses will include descriptive characteristics, static prostate carcinoma, with skeletal lesions end of article. t-tests, effect sizes and two-way (group × time) repeated- identified in >80% of patients with advanced 1–5 Correspondence to measures analysis of variance (or analysis of covariance) prostate cancer. These lesions predomi- Dr Nicolas H Hart; to examine differences between groups over time. The nantly present as sclerotic (osteoblastic) and n. hart@ ecu. edu. au data-set will be primarily examined using an intention-to- primarily reside in the axial skeleton (spine, Hart NH, et al. BMJ Open 2017;7:e014458. doi:10.1136/bmjopen-2016-014458 1 Downloaded from http://bmjopen.bmj.com/ on June 20, 2017 - Published by group.bmj.com Open Access pelvis or ribs),6–8 presenting a considerable challenge Direct loading of animal metastatic bones containing for practitioners to deliver exercise interventions to this human breast cancer tumour cells supports this population.9 10 In particular, advanced cancer patients new direction, successfully interfering with metasta- have historically been excluded from exercise interven- sis-driven tumour formation50 by delivering suppressive tion studies and community-based supervised exercise localised modulatory changes to the tumour microenvi- programmes due to potential adverse skeletal events. ronment, while preserving bone material, structure and Consequently, patients with advanced cancer often fail to strength.49 50 Given the impressive ability of mechanical receive the crucial benefits of exercise in the management loading to epigenetically interfere with metastasis-driven of their disease; that is, to reduce treatment toxicities, tumour formation in osteolytic tumour cells, it is of equal delay disease progression and increase survival through interest to determine whether mechanical loading is also neoadjuvant, adjuvant, synergistic and targeted appli- able to alter metastasis-driven tumour formation in scle- cations. Clinically, bone metastases present as a major rotic tumour cells. This may also prove to be an effective concern with patients experiencing severe bone pain, adjuvant intervention to alleviate bone pain, preserve increased risk of skeletal complications, spinal compres- musculoskeletal strength and suppress sclerotic tumour sion, hypercalcaemia and decreased physical function expansion. To our knowledge, no studies have directly and quality of life.9–13 Subsequently, patients with meta- targeted skeletal metastases in advanced cancer patients static bone disease experience significant morbidity with through controlled, localised exercise programmes in many barriers to exercise participation, thus strategies to order to plausibly modulate tumour biology and suppress safely and effectively reduce the burden of bone meta- tumour growth in humans; nor are we aware of any studies static disease have a high degree of clinical importance. that have specifically established the feasibility or safety Despite the unequivocal benefits of exercise for of loading skeletal sites with sclerotic bone metastases in patients with cancer,14–25 fear of adverse skeletal events patients with advanced prostate cancer. has led to reduced uptake by patients, and reduced refer- The aim of this study is to (1) examine whether a rals to exercise programmes by clinicians9 10 18; a cycle modular multimodal exercise programme with spinal which exacerbates musculoskeletal fragility and tumour isometric training is feasible and safe in patients with progression. In recent times, Galvão and colleagues9 10 21 advanced prostate cancer and sclerotic bone metastases designed a modular, multimodal exercise programme in order to produce targeted and localised adaptations (M3EP) to provide this population with safe and effec- surrounding spinal lesions and (2) examine the prelim- tive exercise modified to avoid direct loading of lesion inary