Measuring the oncological value of exercise and statins (MOVES): Changing the tumour microenvironment with exercise and statins — an exploratory pilot trial

Measuring the oncological value of exercise and statins (MOVES): Changing the tumour microenvironment with exercise and statins — an exploratory pilot trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Measuring the oncological value of exercise and statins (MOVES): Changing the tumour microenvironment with exercise and statins — an exploratory pilot trial Teemu Murtola, Annastiina Hakulinen, Heidi Penttinen, Arja Jukkola, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8501963/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Hypoxia is a critical mechanism by which cancer cells evade the immune response, promoting tumour survival and progression. Many cancer types exhibit upregulated lipid and cholesterol metabolism as a fundamental adaptation strategy to the hypoxic tumour microenvironment. This metabolic shift supports cancer cell survival under oxygen-deprived conditions, enhancing their ability to resist treatment and metastasize. We will explore whether exercise reduces tumour hypoxia via increased systemic and local circulation across four cancer types. We will also test whether atorvastatin, a cholesterol-lowering drug, would further enhance the effects of exercise. We hypothesize that a combined intervention of increased physical activity and atorvastatin may reduce tumour hypoxia. We will also explore associations between changes in tumour hypoxia and clinical outcomes during oncological treatment. Methods The MOVES study is an open-label, randomized, controlled trial. It enrolls 400 adult patients with advanced cancer (prostate, breast, renal, or ovarian) who initiate first-line standard-of-care oncological treatment. Statin-naïve participants are randomized between three arms: (1) supervised exercise with atorvastatin (40 mg once daily) for three months, (2) supervised exercise without atorvastatin, or (3) unsupervised voluntary exercise. Participants who already use statins at the time of recruitment are randomized into two arms: supervised exercise or unsupervised voluntary exercise. The follow-up period extends for 24 months. Outcomes The study will assess tumour hypoxia in primary tumours and metastases using EF5-PET imaging, as well as tumour metabolic activity measured by FDG-PET. Additional assessments include circulating biomarkers of hypoxia and metabolism, tolerability of oncological treatments, body composition, physical performance, quality of life, depressive symptoms, nutritional status, cancer-related pain, personal relationships, progression-free survival, and overall survival. This randomized exploratory study will characterize the tumour-agnostic effects of exercise and metabolic modulation with atorvastatin on tumour hypoxia. Results from the trial will be published in international peer-reviewed journals following study completion, contributing valuable insights into the potential integration of exercise and statin therapy in cancer care. Cancer exercise hypoxia atorvastatin metabolism Figures Figure 1 1. Background Hypoxia in the tumour microenvironment is a common feature in many cancer types. Cancer cell metabolism is adapted to hypoxia (1), as it provides protection against immunological defence; leukocytes act less effectively in a hypoxic environment. Hypoxia also facilitates the development of more aggressive phenotypes, thereby promoting cancer progression. Hypoxia-adapted cancer cells can survive better in circulation and grow more effectively at new locations, leading to the development of metastases. Hypoxia is also a crucial mechanism in resistance to several cancer treatment modalities (2). Thus, reducing hypoxia may improve the results of cancer treatment and reduce disease progression. The conversion of metabolism in cancer cells is a central adaptation mechanism. Well-established changes include a shift in sugar metabolism toward anaerobic glycolysis (the Warburg effect) (1) and an increased use of lipids as an energy source (3). Lipids provide energy efficiently even in a hypoxic microenvironment, allowing cancer cells to survive for longer periods (4). In addition to energy production, lipids also play a role in protecting cancer cells against immunological attacks (5). An increased concentration of intracellular lipids is a shared feature of many cancer types, including renal, breast, and prostate cancer. This increase is caused both by enhanced lipid production within the cells and by increased lipid uptake (6–8). Thus, reducing the supply of lipids to cancer cells and inhibiting their production locally may restrain tumour growth. Exercise provides a means to reduce hypoxia. Adaptation to regular exercise increases systemic circulation, which in turn reduces hypoxia also at the local level in the tumour microenvironment. In mouse models, exercise has been shown to improve circulation in the prostate (9) and to enhance the effectiveness of chemotherapy against breast cancer xenografts (10). In humans, cycling exercise performed three times per week has been shown to affect cancer biomarkers during breast cancer chemotherapy (11). In epidemiological studies, higher levels of physical activity are correlated with improved survival (12). Furthermore, the positive effects of exercise on cancer patients’ quality of life are well established (13). Statins reduce circulating cholesterol levels by inhibiting cholesterol synthesis in the liver as well as the cholesterol-producing mevalonate pathway in cancer cells (14). In epidemiological studies, statin use is consistently associated with a better cancer prognosis compared with nonusers (15). Thus, statins represent an affordable, generally well-tolerated, and easily accessible drug class that may be used to target cholesterol and lipid metabolism in cancer cells. 2. Methods/Design MOVES is a randomized academic clinical trial. The trial will recruit 400 participants with advanced breast, kidney, ovarian, or prostate cancer who are starting first-line standard-of-care therapy for advanced disease. Statin-naïve participants are randomized 1:1:1 into one of three groups: three months of supervised exercise twice per week, three months of supervised exercise combined with atorvastatin 40 mg once daily, or unsupervised voluntary exercise. Participants using statins at the time of recruitment will be randomized 1:1 to either the supervised exercise group or the unsupervised exercise group only (Table 1, Figure 1). Unsupervised groups receive information and material on the benefits of physical exercise but exercise at their own discretion. Study participation is not allowed for individuals considered to be at high risk of bone fractures, those with poor general condition (ECOG ≥2), poor cooperation, severe renal or liver failure, or cytopenia (blood creatinine >170 µmol/l, ALT >2 × ULN, haemoglobin <8 g/dl, neutrophils <1.0 × 10⁹/l, platelets <100 × 10⁹/l). In addition, participants using medications with clinically significant interactions with atorvastatin, or those with other contraindications to atorvastatin use, such as creatine kinase >5 × ULN or hypersensitivity to atorvastatin, are excluded. ***Table 1 here*** ***Table 2 here*** This study will be conducted at Tampere University Hospital, Tampere, Finland. All patients with advanced prostate, renal, breast, or ovarian cancer who fulfil the inclusion criteria will be informed about the study by their treating physician. Patients will receive an information sheet and will be invited to ask questions about the study. Written informed consent will be obtained before inclusion. All enrolled patients will be randomized at the first visit. Participants assigned to the exercise intervention arms will take part in progressive group exercise sessions, including both aerobic and anaerobic training, for 1.5 hours twice per week. They will also receive an individually tailored exercise program from an exercise physiologist with expertise in training cancer patients. Each group exercise session will be supervised by an exercise physiologist at the Varala Sports Centre, Tampere, Finland. Body composition and physical condition will be assessed using standardized tests (30 second chair stand test, forearm flexor test, and mid-trunk flexor test) at baseline, at the end of the intervention (3 months), and after 6 months. *** Figure 1 here *** 3.1. Hypoxia A subset of participants will undergo 18 F-EF5 PET imaging to assess tumour hypoxia at baseline and again at 3 months, allowing evaluation of baseline hypoxia and responses to exercise in the primary tumour and metastases (18). In addition, participants will undergo 18 F-FDG PET imaging at the same time points to assess tumour metabolic activity. Correlations between the two tracers at baseline and after the intervention will be evaluated. All PET–CT scans will be performed at the Turku PET Centre, Turku University Hospital, Turku, Finland. Hypoxia-related and metabolic markers will be studied using blood and urine samples collected at baseline and at 3-month intervals during the 24-month follow-up. Lipidomic and proteomic profiles, levels of the hypoxia markers carbonic anhydrase IX and HIF1α, and expression of hypoxia-activated genes (VEGF, LDHA) will be studied at the protein level. 3.2. Clinical response to treatment Participants will be followed at three-month intervals for up to two years by a study physician. Standard oncologic treatment will be provided according to clinical practice. Imaging studies and laboratory tests will be performed in accordance with the local standard of care (usually at three-month intervals), with the option of shorter intervals at the discretion of the treating clinician. Radiological, clinical, and/or biochemical progression, death, treatment-related side effects, and interruptions of cancer treatment will be recorded. *** Table 3 here *** 3.3. Quality of life, depression, relationships, pain, and nutrition Quality of life will be assessed using a validated questionnaire (EORTC QLQ-C30 (19)), and depression will be measured using the PHQ-9 questionnaire (20) every three months. Pain will be assessed with the Brief Pain Inventory (BPI), and nutritional status will be evaluated using the Mini Nutritional Assessment (MNA) questionnaire (21,22). Relationship status will be assessed using a combination of two validated instruments: the Dyadic Adjustment Scale (DAS) and the Marital Communication Inventory (23–26). A voluntary subset of 48 participants, stratified by trial arm, will be interviewed three times: at baseline, at the end of the exercise intervention, and six months after the end of the intervention. These interviews will qualitatively assess how cancer treatment and exercise affect personal relationships. In addition to the interviews, qualitative data will be collected through participant diaries to capture perceived motivations and barriers to exercise during the intervention. 3.4. Data analysis plan, availability of data and materials This study is the first to test the hypothesis that supervised physical exercise, with or without statin use, can alleviate tumour hypoxia and improve treatment outcomes in patients with advanced cancer. As no prior interventional studies have quantified the effects of exercise or statins on tumour hypoxia using EF5-PET imaging, it is not possible to estimate the sample size based on established effect sizes from previous trials. The planned sample size of 400 participants is therefore based on feasibility considerations and is intended to allow detection of clinically meaningful changes in tumour hypoxia, assuming an approximate 40% reduction associated with exercise (type I error 0.05, power 80%). These assumptions are intended to support feasibility and hypothesis generation rather than confirmatory statistical testing. All outcomes will be analysed using descriptive and inferential statistical methods without a predefined hierarchy between outcome measures. External monitoring will be used. Measurements and medians of measurements will be analysed using a t-test or analysis of variance (ANOVA), or the Mann–Whitney U test or Kruskal–Wallis test, depending on the distribution of the measured values. If a patient is withdrawn from the study, his or her results will be analysed according to the intent-to-treat principle within the study arm to which the patient was originally randomized. The data and materials generated during the study will be made publicly available in anonymized form after publication of the study results. 3.5. Objectives The objective of this study is to explore the effects of supervised, regular exercise including aerobic and strength training on tumour hypoxia during oncological treatment across four cancer types, and to examine whether targeting cholesterol metabolism with atorvastatin modifies these effects. The study will further explore associations between tumour hypoxia and treatment response, survival, treatment tolerability, body composition and physical performance, patients’ quality of life, depressive symptoms, nutritional status, changes in experienced cancer pain, and effects on personal relationships. 3.5. Database, data management, and publishing of the results Study data will be electronically recorded using REDCap, a secure web-based platform. All study data will be pseudonymized, meaning that personal identifiers are replaced with a unique study code. Each member of the research team will receive a personal username and password to access the server, enabling them to process and complete data for study participants. Access to the full database will be restricted to the principal investigator, the research team, and the study monitor, allowing monitoring of study visits and identification of gaps in the stored data. Research registry data will be stored for a minimum of 25 years. If a participant withdraws informed consent, data collected up to the time of withdrawal will be retained as part of the research dataset. Within one year after study completion, the data will be analysed, a clinical study report will be prepared, and the findings will be submitted to the CTIS database. The study results will be published in peer-reviewed international journals. 3.6. Funding This work has been supported by the Pirkanmaa Cancer Association as well as a general grant from the Finnish Academy and the Government Research Funding (VTR). 3.7. Institutional Review Board Statement and Trial Registration The study protocol has been approved by the Institutional Ethics Board of the Pirkanmaa County of Health and Welfare, ETL code R21020M,. Trial registration: EU Clinical Trials Information System (CTIS), EU CT 2024-515109-24-00. 3.8. Informed Consent Statement and consent for publication All participants must provide written informed consent to participate in the study. This consent includes permission for the publication of anonymized data and results derived from the study. 3. Discussion This study is the first to test the hypothesis that supervised physical exercise, with or without statin use, can alleviate tumour hypoxia and thereby improve treatment outcomes in patients with advanced cancer. If the effect of this intervention proves to be as substantial as anticipated, it may meaningfully enhance current cancer care. Because exercise and statins are inexpensive and widely available, they could be incorporated into routine oncology care in a broad range of healthcare settings, including both high-resource and resource-limited environments. If the study hypothesis is supported, the results may help guide the use of structured exercise programs and metabolic modulation as part of supportive care for patients with advanced cancer. As the included cancer types are common, even relatively small improvements in outcomes could translate into meaningful public health benefits. Beyond potential effects on tumour biology and treatment response, supervised exercise may also improve patients’ quality of life, help them tolerate oncological treatments better, and reduce depressive symptoms during therapy. As this study is exploratory in nature, its findings are intended to generate hypotheses and inform the design of future confirmatory trials. Nevertheless, by integrating advanced imaging of tumour hypoxia with clinical, metabolic, and patient-reported outcomes, the study may provide novel insights into the biological and clinical relevance of targeting tumour hypoxia through lifestyle-based interventions. Abbreviations AL(A)T - alanine aminotransferase ANOVA - Analysis of variance BPI - Brief Pain Inventory CD - Cluster of differentiation CT - Computed Tomography DAS - Dyadic Adjustment Scale ECOG - Eastern Cooperative Oncology Group EORTC - European Organization for Research and Treatment of Cancer EWB - Emotional Wellbeing FDG - Fluorodeoxyglucose HIF1α - Hypoxia-inducible factor 1-alpha HRQoL - health-related quality of life IMDC - International Metastatic Renal Cell Carcinoma Database Consortium LADH - Lactic acid dehydrogenase MNA - Mini Nutritional Assessment MOVES – Measuring the oncological value of exercise and statins PET - positron emission tomography PHQ-9 - Patient Health Questionnaire-9 QLQ-C30 - Quality of Life Questionnaire-Core 30 RCC - Renal cell carcinoma SMD - Standardized mean difference VEGF - Vascular Endothelial Growth Factor ULN - Upper limit of normal Declarations Funding This work has been supported by the Pirkanmaa Cancer Association as well as a general grant from the Finnish Academy and the Government Research Funding (VTR). 3.6. Institutional Review Board Statement and Trial Registration The study protocol has been approved by the Institutional Ethics Board of the Pirkanmaa County of Health and Welfare, ETL code R21020M,. Trial registration: EU Clinical Trials Information System (CTIS), EU CT 2024-515109-24-00. 3.7. Informed Consent Statement and consent for publication All participants must provide written informed consent to participate in the study. This consent includes permission for the publication of anonymized data and results derived from the study. 4. Discussion This study is the first to test the hypothesis that supervised physical exercise, with or without statin use, can alleviate tumour hypoxia and thereby improve treatment outcomes in patients with advanced cancer. If the effect of this intervention proves to be as substantial as anticipated, it may meaningfully enhance current cancer care. Because exercise and statins are inexpensive and widely available, they could be incorporated into routine oncology care in a broad range of healthcare settings, including both high-resource and resource-limited environments. If the study hypothesis is supported, the results may help guide the use of structured exercise programs and metabolic modulation as part of supportive care for patients with advanced cancer. As the included cancer types are common, even relatively small improvements in outcomes could translate into meaningful public health benefits. Beyond potential effects on tumour biology and treatment response, supervised exercise may also improve patients’ quality of life, help them tolerate oncological treatments better, and reduce depressive symptoms during therapy. As this study is exploratory in nature, its findings are intended to generate hypotheses and inform the design of future confirmatory trials. Nevertheless, by integrating advanced imaging of tumour hypoxia with clinical, metabolic, and patient-reported outcomes, the study may provide novel insights into the biological and clinical relevance of targeting tumour hypoxia through lifestyle-based interventions. Author Contribution All authors contributed to the study planning and design. All authors participated in manuscript review and protocol writing, critically revising the manuscript for important intellectual content, and approved the final submitted version.JS, TM, and AH contributed to data analysis planning and development, including authorship of the case report forms (CRFs). JK, SM, and VK contributed to the design of the imaging methodology, including PET–CT protocols and imaging endpoints. JS, TM, AA, and SS act as study physicians and are responsible for patient follow-up during the study. All other authors contribute to the identification of potential study participants and referral of eligible patients to the study.JS and TM share overall responsibility for the conception, conduct, and integrity of the study.All authors agree to be personally accountable for their own contributions and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.JS is the corresponding author and confirms that all listed authors have approved the manuscript, the author list, and the order of authors, and that all authors meet the criteria for authorship as defined by the journal. No authors have been added to or removed from the author list during manuscript preparation. References Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. Manoochehri Khoshinani H, Afshar S, Najafi R. Hypoxia: A Double-Edged Sword in Cancer Therapy. Cancer Invest. 2016;34(10):536-545. Yi M, Li J, Chen S et al. Emerging role of lipid metabolism alterations in Cancer stem cells. J Exp Clin Cancer Res. 2018;37(1):118 Metallo CM, Gameiro PA, Bell EL et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2011;481(7381):380-4. Herber DL, Cao W, Nefedova Y et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med. 2010;16(8):880-6. Blücher C, Stadler SC. Obesity and Breast Cancer: Current Insights on the Role of Fatty Acids and Lipid Metabolism in Promoting Breast Cancer Growth and Progression. Front Endocrinol (Lausanne). 2017;8:293. Hakimi AA, Reznik E, Lee CH et al. An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma. Cancer Cell. 2016;29(1):104-116. Krycer JR, Brown AJ. Cholesterol accumulation in prostate cancer: a classic observation from a modern perspective. Biochim Biophys Acta. 2013;1835(2):219-29. Jones LW, Antonelli J, Masko EM et al. Exercise modulation of the host-tumour interaction in an orthotopic model of murine prostate cancer. J Appl Physiol (1985). 2012;113(2):263-72. Betof AS, Lascola CD, Weitzel D et al. Modulation of murine breast tumour vascularity, hypoxia and chemotherapeutic response by exercise. J Natl Cancer Inst. 2015;107(5). Jones LW, Fels DR, West M et al. Modulation of circulating angiogenic factors and tumour biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Cancer Prev Res (Phila). 2013;6(9):925-37. Cormie P, Atkinson M, Bucci L et al. Clinical Oncology Society of Australia position statement on exercise in cancer care. Med J Aust. 2018;209(4):184-187. Mishra SI, Scherer RW, Snyder C et al. Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database Syst Rev. 2012 Aug 15;2012(8):CD008465. doi: 10.1002/14651858.CD008465.pub2. PMID: 22895974; PMCID: PMC7389071. Alfaqih MA, Allott EH, Hamilton RJ, Freeman MR, Freedland SJ. The current evidence on statin use and prostate cancer prevention: are we there yet? Nat Rev Urol. 2017;14(2):107-119. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012;367(19):1792-802. Hunt SJ, Seraj SM, Alavi A. PET Assessment of Immune Effects from Interventional Oncology Procedures. PET Clin. 2019;14(4):477-485. Stieb S, Eleftheriou A, Warnock G, Guckenberger M, Riesterer O. Longitudinal PET imaging of tumour hypoxia during the course of radiotherapy. Eur J Nucl Med Mol Imaging. 2018;45:2201-2217. Chitneni SK, Bida GT, Zalutsky MR, Dewhirst MW. Comparison of the Hypoxia PET Tracer (18)F-EF5 to Immunohistochemical Marker EF5 in 3 Different Human Tumour Xenograft Models. J Nucl Med. 2014 Jul;55(7):1192-7. Apostolova I1, Wedel F2, Brenner W3. Imaging of Tumour Metabolism Using Positron Emission Tomography (PET). Recent Results Cancer Res. 2016;207:177-205. doi: 10.1007/978-3-319-42118-6_8. Le QT, Courter D. Clinical biomarkers for hypoxia targeting. Cancer Metastasis Rev. 2008 ;27:351-62. Miettinen , T , Kautiainen , H , Mantyselka , P , Linton , S J & Kalso , E 2019 , ' Pain interference type and level guide the assessment process in chronic pain : Categorizing pain patients entering tertiary pain treatment with the Brief Pain Inventory ' , PLoS One , vol. 14 , no. 8 , 0221437 . https://doi.org/10.1371/journal.pone.0221437 Helminen, H., Luukkaala, T., Saarnio, J. et al. Predictive value of the mini-nutritional assessment short form (MNA-SF) and nutritional risk screening (NRS2002) in hip fracture. Eur J Clin Nutr 73, 112–120 (2019). https://doi.org/10.1038/s41430-018-0267-y Fayers B, Bottomley A. Quality of life research within the EORTC—the EORTC QLQ-C30. European Journal of Cancer, 2002; 38(4),125-133. https://doi.org/10.1016/S0959-8049(01)00448-8. Kroenke K, Spitzer RL, Williams JB, Löwe B. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. Gen Hosp Psychiatry. 2010 Jul-Aug;32(4):345-59. doi: 10.1016/j.genhosppsych.2010.03.006. Epub 2010 May 7. PMID: 20633738. Spanier G. Measuring dyadic adjustment: new scales for assessing the quality of marriage and simi-lar dyads. 1976; 38, 15-28. Bienvenu M.J.,Sr. Measurement of Marital Communication. The Family Coordinator 1970; 19(1), 26−31. Tables Table 1. Inclusion criteria Inclusion criteria Cancer specific inclusion criteria/definitions 1) The patient has been diagnosed with metastatic prostate, breast, ovarian or kidney cancer, which has been confirmed histologically and by imaging, for which 1st-line cancer drug treatment will be started. Prostate cancer: First course of docetaxel treatment or second-generation antiandrogen treatment for metastatic prostate cancer. - Randomization is stratified by castration resistance: hormone-sensitive vs castration-resistant. Breast cancer: First line treatment for metastatic breast cancer regardless of hormone receptor status. - Randomization is stratified by HER2 status . Kidney cancer: Kidney cancer, for which 1st-line treatment is started with tyrosine kinase inhibitor (tki-) and/or IO monotherapy or as a combination therapy. - Randomization is stratified by gender. Ovarian cancer: Stage III or IV cancer for which chemotherapy will be started. - Randomization is stratified by surgery and residual tumour. 2) The patient consents to the study and signs a written informed consent. 3) Adult (>18 years) females (breast, ovarian, and kidney cancer) and males (prostate and kidney cancer) will be recruited for the study. 4) For women, the use of a reliable contraceptive during the intervention Table 2. Exclusion criteria Exclusion criteria for patients who do not use statin at the time of recruitment Definition 1. High risk of bone fractures Based on the patient's most recent imaging, the attending physician assesses whether there are bone metastases that may cause a risk of fracture in the weight-bearing structures and/or on the femoral neck. Exclusion criteria are also bone metastases that are not under control with pain medication. 2. Inability to physical exertion and/or unsuitability for cancer drug treatment · ECOG value ≥ 2 · Low platelets (B-Trom≤100 x109/l) · Low neutrophils (B-Neut <1 xE9/l) · Low haemoglobin (B-Hb <80 g/l) The treating oncologist evaluates that the patient is not suitable for cancer drug treatment due to his/her condition. 3. Poor co-operation ability for psychological reasons Untreated mental illness, substance abuse, severe personality disorder, or other mental condition that significantly impairs co-operation as assessed by the attending physician. 4. Active use of cholesterol lowering drugs The patient is already using a drug from the statin group or has used it in the last 6 months 5. Severe liver or kidney failure S-ALAT more than twice the reference value or S-Krea more than 170 µmol/l 6. Troublesome side effects that have occurred in the past during cholesterol medication Any side effect previously occurring during cholesterol medication that has led to discontinuation of the medication 7. Continuous use of medicinal substances that interact with atorvastatin during the study period 8. Special group of subjects according to the Clinical trials regulation (EU) No 536/2014 (e.g. pregnant or lactating women) The medicinal substances in question are: St. John's wort, protease inhibitors used to treat HIV infection (e.g. ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir), ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, gemfibrozil and other fibric acid derivatives, macrolide antibiotics, fusidic acid, phenytoin, carbamazepine, dronedarone, oral antifungals, antivirals used to treat hepatitis C (e.g. boseprevis, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir), erythromycin, niacin and ezetimibe Exclusion criteria for patients who use statin at the time of recruitment Definition 1. High risk of bone fractures Based on the patient's most recent imaging, the attending physician assesses whether there are bone metastases that may cause a risk of fracture in the weight-bearing structures and/or on the femoral neck. Exclusion criteria are also bone metastases that are not under control with pain medication. 2. Inability to physical exertion and/or unsuitability for cancer drug treatment · ECOG value ≥ 2, in addition · Low platelets (B-Trom≤100 x109/l) · Low neutrophils (B-Neut <1 xE9/l) · Low haemoglobin (B-Hb <80 g/l) The treating oncologist evaluates that the patient is not suitable for cancer drug treatment due to his/her condition. 3. Poor co-operation ability for psychological reasons Untreated mental illness, substance abuse, severe personality disorder, or other mental condition that significantly impairs co-operation as assessed by the attending physician. 4. Severe liver or kidney failure S-ALAT more than twice the reference value or S-Krea more than 170 µmol/l 5. Special group of subjects according to the Clinical trials regulation (EU) No 536/2014 (e.g. pregnant or lactating women) Table 3. The course of the study and the contents of the study visits. Selection visit Initial visit Follow-up visits every 3 months Final visit 0 mo 3 mo 6 mo 9 mo etc. 24 mo Evaluation of suitability for the study x Presentation of study content x Informed consent x Randomization x Alkaline phosphatase x x x x x Creatinine x x x x x Serum creatinine kinase x x* x* x* x* Alanine aminotransferase x x* x* x* x* Serum Lipids x x x x x Fasting blood glucose x x x x x Storage blood sample x x x x x Urine sample x x x x x x x x x x Quality of life questionnaires x x x x x Physical condition measurement x x x Body composition measurement x x x Blood pressure x x x x x Subgroups Interviews x x x Brief Pain Inventory questionnaire x x x x x Mini Nutritional Assessment questionnaire x x x x x PET-CT-scanning x x Prostate Specific Antigen** x x x x x CA15-3 -measurement*** x x x x x CA12-5 -measurement**** x x x x x * Only measured of patients randomized to statin-group ** ** Only measured for prostate cancer patients *** Only measured for breast cancer patients **** Only measured for ovarian cancer patients Additional Declarations No competing interests reported. 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15:38:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8501963/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8501963/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101398217,"identity":"402584c7-2697-42d2-8f86-b5aa65471b07","added_by":"auto","created_at":"2026-01-29 09:40:18","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":167517,"visible":true,"origin":"","legend":"\u003cp\u003eStudy layout and research flow\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8501963/v1/ee448ba12d910e31afd06022.png"},{"id":101751202,"identity":"759f15c8-3282-4266-90a2-a84221180f62","added_by":"auto","created_at":"2026-02-03 10:18:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":744512,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8501963/v1/3f4379f4-8e5f-4cdc-9cdf-826af2b39981.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Measuring the oncological value of exercise and statins (MOVES): Changing the tumour microenvironment with exercise and statins — an exploratory pilot trial","fulltext":[{"header":"1. Background","content":"\u003cp\u003eHypoxia in the tumour microenvironment is a common feature in many cancer types. Cancer cell metabolism is adapted to hypoxia (1), as it provides protection against immunological defence; leukocytes act less effectively in a hypoxic environment. Hypoxia also facilitates the development of more aggressive phenotypes, thereby promoting cancer progression. Hypoxia-adapted cancer cells can survive better in circulation and grow more effectively at new locations, leading to the development of metastases. Hypoxia is also a crucial mechanism in resistance to several cancer treatment modalities (2). Thus, reducing hypoxia may improve the results of cancer treatment and reduce disease progression.\u003c/p\u003e\n\u003cp\u003eThe conversion of metabolism in cancer cells is a central adaptation mechanism. Well-established changes include a shift in sugar metabolism toward anaerobic glycolysis (the Warburg effect) (1) and an increased use of lipids as an energy source (3). Lipids provide energy efficiently even in a hypoxic microenvironment, allowing cancer cells to survive for longer periods (4). In addition to energy production, lipids also play a role in protecting cancer cells against immunological attacks (5).\u003c/p\u003e\n\u003cp\u003eAn increased concentration of intracellular lipids is a shared feature of many cancer types, including renal, breast, and prostate cancer. This increase is caused both by enhanced lipid production within the cells and by increased lipid uptake (6–8). Thus, reducing the supply of lipids to cancer cells and inhibiting their production locally may restrain tumour growth.\u003c/p\u003e\n\u003cp\u003eExercise provides a means to reduce hypoxia. Adaptation to regular exercise increases systemic circulation, which in turn reduces hypoxia also at the local level in the tumour microenvironment. In mouse models, exercise has been shown to improve circulation in the prostate (9) and to enhance the effectiveness of chemotherapy against breast cancer xenografts (10). In humans, cycling exercise performed three times per week has been shown to affect cancer biomarkers during breast cancer chemotherapy (11). In epidemiological studies, higher levels of physical activity are correlated with improved survival (12). Furthermore, the positive effects of exercise on cancer patients’ quality of life are well established (13).\u003c/p\u003e\n\u003cp\u003eStatins reduce circulating cholesterol levels by inhibiting cholesterol synthesis in the liver as well as the cholesterol-producing mevalonate pathway in cancer cells (14). In epidemiological studies, statin use is consistently associated with a better cancer prognosis compared with nonusers (15). Thus, statins represent an affordable, generally well-tolerated, and easily accessible drug class that may be used to target cholesterol and lipid metabolism in cancer cells.\u003c/p\u003e"},{"header":"2.\tMethods/Design","content":"\u003cp\u003eMOVES is a randomized academic clinical trial. The trial will recruit 400 participants with advanced breast, kidney, ovarian, or prostate cancer who are starting first-line standard-of-care therapy for advanced disease. Statin-naïve participants are randomized 1:1:1 into one of three groups: three months of supervised exercise twice per week, three months of supervised exercise combined with atorvastatin 40 mg once daily, or unsupervised voluntary exercise. Participants using statins at the time of recruitment will be randomized 1:1 to either the supervised exercise group or the unsupervised exercise group only (Table 1, Figure 1). Unsupervised groups receive information and material on the benefits of physical exercise but exercise at their own discretion.\u003c/p\u003e\n\u003cp\u003eStudy participation is not allowed for individuals considered to be at high risk of bone fractures, those with poor general condition (ECOG ≥2), poor cooperation, severe renal or liver failure, or cytopenia (blood creatinine \u0026gt;170 µmol/l, ALT \u0026gt;2 × ULN, haemoglobin \u0026lt;8 g/dl, neutrophils \u0026lt;1.0 × 10⁹/l, platelets \u0026lt;100 × 10⁹/l). In addition, participants using medications with clinically significant interactions with atorvastatin, or those with other contraindications to atorvastatin use, such as creatine kinase \u0026gt;5 × ULN or hypersensitivity to atorvastatin, are excluded.\u003c/p\u003e\n\u003cp\u003e***Table 1 here*** \u003c/p\u003e\n\u003cp\u003e***Table 2 here***\u003c/p\u003e\n\u003cp\u003eThis study will be conducted at Tampere University Hospital, Tampere, Finland. All patients with advanced prostate, renal, breast, or ovarian cancer who fulfil the inclusion criteria will be informed about the study by their treating physician. Patients will receive an information sheet and will be invited to ask questions about the study. Written informed consent will be obtained before inclusion. All enrolled patients will be randomized at the first visit.\u003c/p\u003e\n\u003cp\u003eParticipants assigned to the exercise intervention arms will take part in progressive group exercise sessions, including both aerobic and anaerobic training, for 1.5 hours twice per week. They will also receive an individually tailored exercise program from an exercise physiologist with expertise in training cancer patients. Each group exercise session will be supervised by an exercise physiologist at the Varala Sports Centre, Tampere, Finland. Body composition and physical condition will be assessed using standardized tests (30 second chair stand test, forearm flexor test, and mid-trunk flexor test) at baseline, at the end of the intervention (3 months), and after 6 months.\u003c/p\u003e\n\u003cp\u003e*** Figure 1 here ***\u003c/p\u003e\n\u003cp\u003e3.1. Hypoxia\u003c/p\u003e\n\u003cp\u003eA subset of participants will undergo \u003csup\u003e18\u003c/sup\u003eF-EF5 PET imaging to assess tumour hypoxia at baseline and again at 3 months, allowing evaluation of baseline hypoxia and responses to exercise in the primary tumour and metastases (18). In addition, participants will undergo \u003csup\u003e18\u003c/sup\u003eF-FDG PET imaging at the same time points to assess tumour metabolic activity. Correlations between the two tracers at baseline and after the intervention will be evaluated. All PET–CT scans will be performed at the Turku PET Centre, Turku University Hospital, Turku, Finland.\u003c/p\u003e\n\u003cp\u003eHypoxia-related and metabolic markers will be studied using blood and urine samples collected at baseline and at 3-month intervals during the 24-month follow-up. Lipidomic and proteomic profiles, levels of the hypoxia markers carbonic anhydrase IX and HIF1α, and expression of hypoxia-activated genes (VEGF, LDHA) will be studied at the protein level.\u003c/p\u003e\n\u003cp\u003e3.2. Clinical response to treatment\u003c/p\u003e\n\u003cp\u003eParticipants will be followed at three-month intervals for up to two years by a study physician. Standard oncologic treatment will be provided according to clinical practice. Imaging studies and laboratory tests will be performed in accordance with the local standard of care (usually at three-month intervals), with the option of shorter intervals at the discretion of the treating clinician. Radiological, clinical, and/or biochemical progression, death, treatment-related side effects, and interruptions of cancer treatment will be recorded.\u003c/p\u003e\n\u003cp\u003e*** Table 3 here ***\u003c/p\u003e\n\u003cp\u003e3.3. Quality of life, depression, relationships, pain, and nutrition\u003c/p\u003e\n\u003cp\u003eQuality of life will be assessed using a validated questionnaire (EORTC QLQ-C30 (19)), and depression will be measured using the PHQ-9 questionnaire (20) every three months. Pain will be assessed with the Brief Pain Inventory (BPI), and nutritional status will be evaluated using the Mini Nutritional Assessment (MNA) questionnaire (21,22). Relationship status will be assessed using a combination of two validated instruments: the Dyadic Adjustment Scale (DAS) and the Marital Communication Inventory (23–26).\u003c/p\u003e\n\u003cp\u003eA voluntary subset of 48 participants, stratified by trial arm, will be interviewed three times: at baseline, at the end of the exercise intervention, and six months after the end of the intervention. These interviews will qualitatively assess how cancer treatment and exercise affect personal relationships. In addition to the interviews, qualitative data will be collected through participant diaries to capture perceived motivations and barriers to exercise during the intervention.\u003c/p\u003e\n\u003cp\u003e3.4. Data analysis plan, availability of data and materials\u003c/p\u003e\n\u003cp\u003eThis study is the first to test the hypothesis that supervised physical exercise, with or without statin use, can alleviate tumour hypoxia and improve treatment outcomes in patients with advanced cancer. As no prior interventional studies have quantified the effects of exercise or statins on tumour hypoxia using EF5-PET imaging, it is not possible to estimate the sample size based on established effect sizes from previous trials. The planned sample size of 400 participants is therefore based on feasibility considerations and is intended to allow detection of clinically meaningful changes in tumour hypoxia, assuming an approximate 40% reduction associated with exercise (type I error 0.05, power 80%). These assumptions are intended to support feasibility and hypothesis generation rather than confirmatory statistical testing.\u003c/p\u003e\n\u003cp\u003eAll outcomes will be analysed using descriptive and inferential statistical methods without a predefined hierarchy between outcome measures.\u003c/p\u003e\n\u003cp\u003eExternal monitoring will be used. Measurements and medians of measurements will be analysed using a t-test or analysis of variance (ANOVA), or the Mann–Whitney U test or Kruskal–Wallis test, depending on the distribution of the measured values. If a patient is withdrawn from the study, his or her results will be analysed according to the intent-to-treat principle within the study arm to which the patient was originally randomized. The data and materials generated during the study will be made publicly available in anonymized form after publication of the study results.\u003c/p\u003e\n\u003cp\u003e3.5. Objectives\u003c/p\u003e\n\u003cp\u003eThe objective of this study is to explore the effects of supervised, regular exercise including aerobic and strength training on tumour hypoxia during oncological treatment across four cancer types, and to examine whether targeting cholesterol metabolism with atorvastatin modifies these effects. The study will further explore associations between tumour hypoxia and treatment response, survival, treatment tolerability, body composition and physical performance, patients’ quality of life, depressive symptoms, nutritional status, changes in experienced cancer pain, and effects on personal relationships.\u003c/p\u003e\n\u003cp\u003e3.5. Database, data management, and publishing of the results\u003c/p\u003e\n\u003cp\u003eStudy data will be electronically recorded using REDCap, a secure web-based platform. All study data will be pseudonymized, meaning that personal identifiers are replaced with a unique study code. Each member of the research team will receive a personal username and password to access the server, enabling them to process and complete data for study participants. Access to the full database will be restricted to the principal investigator, the research team, and the study monitor, allowing monitoring of study visits and identification of gaps in the stored data. Research registry data will be stored for a minimum of 25 years. If a participant withdraws informed consent, data collected up to the time of withdrawal will be retained as part of the research dataset.\u003c/p\u003e\n\u003cp\u003eWithin one year after study completion, the data will be analysed, a clinical study report will be prepared, and the findings will be submitted to the CTIS database. The study results will be published in peer-reviewed international journals.\u003c/p\u003e\n\u003cp\u003e3.6. Funding\u003c/p\u003e\n\u003cp\u003eThis work has been supported by the Pirkanmaa Cancer Association as well as a general grant from the Finnish Academy and the Government Research Funding (VTR).\u003c/p\u003e\n\u003cp\u003e3.7. Institutional Review Board Statement and Trial Registration\u003c/p\u003e\n\u003cp\u003eThe study protocol has been approved by the Institutional Ethics Board of the Pirkanmaa County of Health and Welfare, ETL code R21020M,. Trial registration: EU Clinical Trials Information System (CTIS), EU CT 2024-515109-24-00. \u003c/p\u003e\n\u003cp\u003e3.8. Informed Consent Statement and consent for publication\u003c/p\u003e\n\u003cp\u003eAll participants must provide written informed consent to participate in the study. This consent includes permission for the publication of anonymized data and results derived from the study.\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eThis study is the first to test the hypothesis that supervised physical exercise, with or without statin use, can alleviate tumour hypoxia and thereby improve treatment outcomes in patients with advanced cancer. If the effect of this intervention proves to be as substantial as anticipated, it may meaningfully enhance current cancer care.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBecause exercise and statins are inexpensive and widely available, they could be incorporated into routine oncology care in a broad range of healthcare settings, including both high-resource and resource-limited environments. If the study hypothesis is supported, the results may help guide the use of structured exercise programs and metabolic modulation as part of supportive care for patients with advanced cancer. As the included cancer types are common, even relatively small improvements in outcomes could translate into meaningful public health benefits. Beyond potential effects on tumour biology and treatment response, supervised exercise may also improve patients’ quality of life, help them tolerate oncological treatments better, and reduce depressive symptoms during therapy.\u003c/p\u003e\n\u003cp\u003eAs this study is exploratory in nature, its findings are intended to generate hypotheses and inform the design of future confirmatory trials. Nevertheless, by integrating advanced imaging of tumour hypoxia with clinical, metabolic, and patient-reported outcomes, the study may provide novel insights into the biological and clinical relevance of targeting tumour hypoxia through lifestyle-based interventions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAL(A)T -\u0026nbsp;alanine aminotransferase\u003c/p\u003e\n\u003cp\u003eANOVA - Analysis of\u0026nbsp;variance\u003c/p\u003e\n\u003cp\u003eBPI - Brief Pain Inventory\u003c/p\u003e\n\u003cp\u003eCD - Cluster of\u0026nbsp;differentiation\u003c/p\u003e\n\u003cp\u003eCT - Computed Tomography\u003c/p\u003e\n\u003cp\u003eDAS - Dyadic Adjustment Scale\u003c/p\u003e\n\u003cp\u003eECOG - Eastern Cooperative Oncology Group\u003c/p\u003e\n\u003cp\u003eEORTC - European Organization for Research and Treatment of Cancer\u003c/p\u003e\n\u003cp\u003eEWB - Emotional Wellbeing\u003c/p\u003e\n\u003cp\u003eFDG - Fluorodeoxyglucose\u003c/p\u003e\n\u003cp\u003eHIF1\u0026alpha; - Hypoxia-inducible factor\u0026nbsp;1-alpha\u003c/p\u003e\n\u003cp\u003eHRQoL -\u0026nbsp;health-related quality of life\u003c/p\u003e\n\u003cp\u003eIMDC - International Metastatic Renal Cell Carcinoma Database Consortium\u003c/p\u003e\n\u003cp\u003eLADH - Lactic\u0026nbsp;acid dehydrogenase\u003c/p\u003e\n\u003cp\u003eMNA - Mini Nutritional Assessment\u003c/p\u003e\n\u003cp\u003eMOVES \u0026ndash; Measuring the\u0026nbsp;oncological value of exercise and statins\u003c/p\u003e\n\u003cp\u003ePET -\u0026nbsp;positron emission tomography\u003c/p\u003e\n\u003cp\u003ePHQ-9 - Patient Health Questionnaire-9\u003c/p\u003e\n\u003cp\u003eQLQ-C30 - Quality of Life Questionnaire-Core 30\u003c/p\u003e\n\u003cp\u003eRCC - Renal\u0026nbsp;cell carcinoma\u003c/p\u003e\n\u003cp\u003eSMD - Standardized\u0026nbsp;mean difference\u003c/p\u003e\n\u003cp\u003eVEGF - Vascular Endothelial Growth Factor\u003c/p\u003e\n\u003cp\u003eULN - Upper limit of normal\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work has been supported by the Pirkanmaa Cancer Association as well as a general grant from the Finnish Academy and the Government Research Funding (VTR).\u003c/p\u003e \u003cp\u003e3.6. Institutional Review Board Statement and Trial Registration\u003c/p\u003e \u003cp\u003e The study protocol has been approved by the Institutional Ethics Board of the Pirkanmaa County of Health and Welfare, ETL code R21020M,. Trial registration: EU Clinical Trials Information System (CTIS), EU CT 2024-515109-24-00.\u003c/p\u003e \u003cp\u003e3.7. Informed Consent Statement and consent for publication\u003c/p\u003e \u003cp\u003e All participants must provide written informed consent to participate in the study. This consent includes permission for the publication of anonymized data and results derived from the study.\u003c/p\u003e \u003cp\u003e4. Discussion\u003c/p\u003e \u003cp\u003eThis study is the first to test the hypothesis that supervised physical exercise, with or without statin use, can alleviate tumour hypoxia and thereby improve treatment outcomes in patients with advanced cancer. If the effect of this intervention proves to be as substantial as anticipated, it may meaningfully enhance current cancer care.\u003c/p\u003e \u003cp\u003eBecause exercise and statins are inexpensive and widely available, they could be incorporated into routine oncology care in a broad range of healthcare settings, including both high-resource and resource-limited environments. If the study hypothesis is supported, the results may help guide the use of structured exercise programs and metabolic modulation as part of supportive care for patients with advanced cancer. As the included cancer types are common, even relatively small improvements in outcomes could translate into meaningful public health benefits. Beyond potential effects on tumour biology and treatment response, supervised exercise may also improve patients\u0026rsquo; quality of life, help them tolerate oncological treatments better, and reduce depressive symptoms during therapy.\u003c/p\u003e \u003cp\u003eAs this study is exploratory in nature, its findings are intended to generate hypotheses and inform the design of future confirmatory trials. Nevertheless, by integrating advanced imaging of tumour hypoxia with clinical, metabolic, and patient-reported outcomes, the study may provide novel insights into the biological and clinical relevance of targeting tumour hypoxia through lifestyle-based interventions.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study planning and design. All authors participated in manuscript review and protocol writing, critically revising the manuscript for important intellectual content, and approved the final submitted version.JS, TM, and AH contributed to data analysis planning and development, including authorship of the case report forms (CRFs). JK, SM, and VK contributed to the design of the imaging methodology, including PET\u0026ndash;CT protocols and imaging endpoints. JS, TM, AA, and SS act as study physicians and are responsible for patient follow-up during the study. All other authors contribute to the identification of potential study participants and referral of eligible patients to the study.JS and TM share overall responsibility for the conception, conduct, and integrity of the study.All authors agree to be personally accountable for their own contributions and to ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.JS is the corresponding author and confirms that all listed authors have approved the manuscript, the author list, and the order of authors, and that all authors meet the criteria for authorship as defined by the journal. No authors have been added to or removed from the author list during manuscript preparation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74.\u003c/li\u003e\n\u003cli\u003eManoochehri Khoshinani H, Afshar S, Najafi R. Hypoxia: A Double-Edged Sword in Cancer Therapy. Cancer Invest. 2016;34(10):536-545.\u003c/li\u003e\n\u003cli\u003eYi M, Li J, Chen S et al. Emerging role of lipid metabolism alterations in Cancer stem cells. J Exp Clin Cancer Res. 2018;37(1):118\u003c/li\u003e\n\u003cli\u003eMetallo CM, Gameiro PA, Bell EL et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2011;481(7381):380-4.\u003c/li\u003e\n\u003cli\u003eHerber DL, Cao W, Nefedova Y et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med. 2010;16(8):880-6.\u003c/li\u003e\n\u003cli\u003eBl\u0026uuml;cher C, Stadler SC. Obesity and Breast Cancer: Current Insights on the Role of Fatty Acids and Lipid Metabolism in Promoting Breast Cancer Growth and Progression. Front Endocrinol (Lausanne). 2017;8:293.\u003c/li\u003e\n\u003cli\u003eHakimi AA, Reznik E, Lee CH et al. An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma. Cancer Cell. 2016;29(1):104-116.\u003c/li\u003e\n\u003cli\u003eKrycer JR, Brown AJ. Cholesterol accumulation in prostate cancer: a classic observation from a modern perspective. Biochim Biophys Acta. 2013;1835(2):219-29.\u003c/li\u003e\n\u003cli\u003eJones LW, Antonelli J, Masko EM et al. Exercise modulation of the host-tumour interaction in an orthotopic model of murine prostate cancer. J Appl Physiol (1985). 2012;113(2):263-72.\u003c/li\u003e\n\u003cli\u003eBetof AS, Lascola CD, Weitzel D et al. Modulation of murine breast tumour vascularity, hypoxia and chemotherapeutic response by exercise. J Natl Cancer Inst. 2015;107(5).\u003c/li\u003e\n\u003cli\u003eJones LW, Fels DR, West M et al. Modulation of circulating angiogenic factors and tumour biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Cancer Prev Res (Phila). 2013;6(9):925-37.\u003c/li\u003e\n\u003cli\u003eCormie P, Atkinson M, Bucci L et al. Clinical Oncology Society of Australia position statement on exercise in cancer care. Med J Aust. 2018;209(4):184-187.\u003c/li\u003e\n\u003cli\u003eMishra SI, Scherer RW, Snyder C et al. Exercise interventions on health-related quality of life for people with cancer during active treatment. Cochrane Database Syst Rev. 2012 Aug 15;2012(8):CD008465. doi: 10.1002/14651858.CD008465.pub2. PMID: 22895974; PMCID: PMC7389071.\u003c/li\u003e\n\u003cli\u003eAlfaqih MA, Allott EH, Hamilton RJ, Freeman MR, Freedland SJ. The current evidence on statin use and prostate cancer prevention: are we there yet? Nat Rev Urol. 2017;14(2):107-119.\u003c/li\u003e\n\u003cli\u003eNielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med. 2012;367(19):1792-802.\u003c/li\u003e\n\u003cli\u003eHunt SJ, Seraj SM, Alavi A. PET Assessment of Immune Effects from Interventional Oncology Procedures. PET Clin. 2019;14(4):477-485.\u003c/li\u003e\n\u003cli\u003eStieb S, Eleftheriou A, Warnock G, Guckenberger M, Riesterer O. Longitudinal PET imaging of tumour hypoxia during the course of radiotherapy. Eur J Nucl Med Mol Imaging. 2018;45:2201-2217.\u003c/li\u003e\n\u003cli\u003eChitneni SK, Bida GT, Zalutsky MR, Dewhirst MW. Comparison of the Hypoxia PET Tracer (18)F-EF5 to Immunohistochemical Marker EF5 in 3 Different Human Tumour Xenograft Models. J Nucl Med. 2014 Jul;55(7):1192-7.\u003c/li\u003e\n\u003cli\u003eApostolova I1, Wedel F2, Brenner W3. Imaging of Tumour Metabolism Using Positron Emission Tomography (PET). Recent Results Cancer Res. 2016;207:177-205. doi: 10.1007/978-3-319-42118-6_8.\u003c/li\u003e\n\u003cli\u003eLe QT, Courter D. Clinical biomarkers for hypoxia targeting. Cancer Metastasis Rev. 2008 ;27:351-62.\u003c/li\u003e\n\u003cli\u003eMiettinen , T , Kautiainen , H , Mantyselka , P , Linton , S J \u0026amp; Kalso , E 2019 , \u0026apos; Pain interference type and level guide the assessment process in chronic pain : Categorizing pain patients entering tertiary pain treatment with the Brief Pain Inventory \u0026apos; , PLoS One , vol. 14 , no. 8 , 0221437 . https://doi.org/10.1371/journal.pone.0221437\u003c/li\u003e\n\u003cli\u003eHelminen, H., Luukkaala, T., Saarnio, J. et al. Predictive value of the mini-nutritional assessment short form (MNA-SF) and nutritional risk screening (NRS2002) in hip fracture. Eur J Clin Nutr 73, 112\u0026ndash;120 (2019). https://doi.org/10.1038/s41430-018-0267-y\u003c/li\u003e\n\u003cli\u003eFayers B, Bottomley A. Quality of life research within the EORTC\u0026mdash;the EORTC QLQ-C30. European Journal of Cancer, 2002; 38(4),125-133. https://doi.org/10.1016/S0959-8049(01)00448-8.\u003c/li\u003e\n\u003cli\u003eKroenke K, Spitzer RL, Williams JB, L\u0026ouml;we B. The Patient Health Questionnaire Somatic, Anxiety, and Depressive Symptom Scales: a systematic review. Gen Hosp Psychiatry. 2010 Jul-Aug;32(4):345-59. doi: 10.1016/j.genhosppsych.2010.03.006. Epub 2010 May 7. PMID: 20633738.\u003c/li\u003e\n\u003cli\u003eSpanier G. Measuring dyadic adjustment: new scales for assessing the quality of marriage and simi-lar dyads. 1976; 38, 15-28.\u003c/li\u003e\n\u003cli\u003eBienvenu M.J.,Sr. Measurement of Marital Communication. The Family Coordinator 1970; 19(1), 26\u0026minus;31.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Inclusion criteria\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 45.5814%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54.2636%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCancer specific inclusion criteria/definitions\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 45.5814%;\"\u003e\n \u003cp\u003e1) The patient has been diagnosed with metastatic prostate, breast, ovarian or kidney cancer, which has been confirmed histologically and by imaging, for which 1st-line cancer drug treatment will be started.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54.2636%;\"\u003e\n \u003cp\u003e\u003cem\u003eProstate cancer:\u0026nbsp;\u003c/em\u003eFirst course of docetaxel treatment or second-generation antiandrogen treatment for metastatic prostate cancer.\u003c/p\u003e\n \u003cp\u003e- Randomization is stratified by castration resistance: hormone-sensitive vs castration-resistant.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003eBreast cancer:\u0026nbsp;\u003c/em\u003eFirst line treatment for metastatic breast cancer regardless of hormone receptor status.\u003c/p\u003e\n \u003cp\u003e- Randomization is stratified by HER2 status\u003cem\u003e.\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003eKidney cancer:\u0026nbsp;\u003c/em\u003eKidney cancer, for which 1st-line treatment is started with tyrosine kinase inhibitor (tki-) and/or IO monotherapy or as a combination therapy.\u003c/p\u003e\n \u003cp\u003e- Randomization is stratified by gender.\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003eOvarian cancer:\u0026nbsp;\u003c/em\u003eStage III or IV cancer for which chemotherapy will be started.\u003c/p\u003e\n \u003cp\u003e- Randomization is stratified by surgery and residual tumour.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 45.5814%;\"\u003e\n \u003cp\u003e2) The patient consents to the study and signs a written informed consent.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;3) Adult (\u0026gt;18 years) females (breast, ovarian, and kidney cancer) and males (prostate and kidney cancer) will be recruited for the study.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;4) For women, the use of a reliable contraceptive during the intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 54.2636%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 2. Exclusion criteria\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eExclusion criteria for patients who do not use statin at the time of recruitment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eDefinition\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e1. High risk of bone fractures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eBased on the patient\u0026apos;s most recent imaging, the attending physician assesses whether there are bone metastases that may cause a risk of fracture in the weight-bearing structures and/or on the femoral neck. Exclusion criteria are also bone metastases that are not under control with pain medication.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e2. Inability to physical exertion and/or unsuitability for cancer drug treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003e\u0026middot; ECOG value \u0026ge; 2\u003c/p\u003e\n \u003cp\u003e\u0026middot; Low platelets (B-Trom\u0026le;100 x109/l)\u003c/p\u003e\n \u003cp\u003e\u0026middot; Low neutrophils (B-Neut \u0026lt;1 xE9/l)\u003c/p\u003e\n \u003cp\u003e\u0026middot; Low haemoglobin (B-Hb \u0026lt;80 g/l)\u003c/p\u003e\n \u003cp\u003eThe treating oncologist evaluates that the patient is not suitable for cancer drug treatment due to his/her condition.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e3. Poor co-operation ability for psychological reasons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eUntreated mental illness, substance abuse, severe personality disorder, or other mental condition that significantly impairs co-operation as assessed by the attending physician.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e4. Active use of cholesterol lowering drugs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eThe patient is already using a drug from the statin group or has used it in the last 6 months\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e5. \u0026nbsp; \u0026nbsp;Severe liver or kidney failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eS-ALAT more than twice the reference value or S-Krea more than 170 \u0026micro;mol/l\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e6. \u0026nbsp; \u0026nbsp; Troublesome side effects that have occurred in the past during cholesterol medication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eAny side effect previously occurring during cholesterol medication that has led to discontinuation of the medication\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e7. \u0026nbsp; \u0026nbsp;Continuous use of medicinal substances that interact with atorvastatin during the study period\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8. \u0026nbsp; \u0026nbsp;Special group of subjects according to the Clinical trials regulation (EU) No 536/2014 (e.g. pregnant or lactating women)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eThe medicinal substances in question are: St. John\u0026apos;s wort, protease inhibitors used to treat HIV infection (e.g. ritonavir, lopinavir, atazanavir, indinavir, darunavir, tipranavir/ritonavir), ciclosporin, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, letermovir, gemfibrozil and other fibric acid derivatives,\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; macrolide antibiotics, fusidic acid, phenytoin, carbamazepine, dronedarone, oral antifungals, antivirals used to treat hepatitis C (e.g. boseprevis, telaprevir, elbasvir/grazoprevir, ledipasvir/sofosbuvir), erythromycin, niacin and ezetimibe\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eExclusion criteria for patients who use statin at the time of recruitment\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eDefinition\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e1. High risk of bone fractures\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eBased on the patient\u0026apos;s most recent imaging, the attending physician assesses whether there are bone metastases that may cause a risk of fracture in the weight-bearing structures and/or on the femoral neck. Exclusion criteria are also bone metastases that are not under control with pain medication.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e2. Inability to physical exertion and/or unsuitability for cancer drug treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003e\u0026middot; ECOG value \u0026ge; 2, in addition\u003c/p\u003e\n \u003cp\u003e\u0026middot; Low platelets (B-Trom\u0026le;100 x109/l)\u003c/p\u003e\n \u003cp\u003e\u0026middot; Low neutrophils (B-Neut \u0026lt;1 xE9/l)\u003c/p\u003e\n \u003cp\u003e\u0026middot; Low haemoglobin (B-Hb \u0026lt;80 g/l)\u003c/p\u003e\n \u003cp\u003eThe treating oncologist evaluates that the patient is not suitable for cancer drug treatment due to his/her condition.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e3. Poor co-operation ability for psychological reasons\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eUntreated mental illness, substance abuse, severe personality disorder, or other mental condition that significantly impairs co-operation as assessed by the attending physician.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e4. Severe liver or kidney failure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003eS-ALAT more than twice the reference value or S-Krea more than 170 \u0026micro;mol/l\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e5. Special group of subjects according to the Clinical trials regulation (EU) No 536/2014 (e.g. pregnant or lactating women)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 340px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eTable 3. The course of the study and the contents of the study visits.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSelection visit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInitial visit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eFollow-up visits every 3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFinal visit\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0 mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 mo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 mo etc.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e24 mo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEvaluation of suitability for the study\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePresentation of study content\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRandomization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAlkaline phosphatase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCreatinine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSerum creatinine kinase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAlanine aminotransferase\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSerum Lipids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFasting blood glucose\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eStorage blood sample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eUrine sample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eQuality of life questionnaires\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePhysical condition measurement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBody composition measurement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBlood pressure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSubgroups\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInterviews\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBrief Pain Inventory questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMini Nutritional Assessment questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePET-CT-scanning\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eProstate Specific Antigen**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCA15-3 -measurement***\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCA12-5 -measurement****\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ex\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e* Only measured of patients randomized to statin-group\u003c/p\u003e\n \u003cp\u003e**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e** Only measured for prostate cancer patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e*** Only measured for breast cancer patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\"\u003e\n \u003cp\u003e**** Only measured for ovarian cancer patients\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cancer, exercise, hypoxia, atorvastatin, metabolism","lastPublishedDoi":"10.21203/rs.3.rs-8501963/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8501963/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHypoxia is a critical mechanism by which cancer cells evade the immune response, promoting tumour survival and progression. Many cancer types exhibit upregulated lipid and cholesterol metabolism as a fundamental adaptation strategy to the hypoxic tumour microenvironment. This metabolic shift supports cancer cell survival under oxygen-deprived conditions, enhancing their ability to resist treatment and metastasize.\u003c/p\u003e\n\u003cp\u003eWe will explore whether exercise reduces tumour hypoxia via increased systemic and local circulation across four cancer types. We will also test whether atorvastatin, a cholesterol-lowering drug, would further enhance the effects of exercise. We hypothesize that a combined intervention of increased physical activity and atorvastatin may reduce tumour hypoxia. We will also explore associations between changes in tumour hypoxia and clinical outcomes during oncological treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe MOVES study is an open-label, randomized, controlled trial. It enrolls 400 adult patients with advanced cancer (prostate, breast, renal, or ovarian) who initiate first-line standard-of-care oncological treatment. Statin-naïve participants are randomized between three arms: (1) supervised exercise with atorvastatin (40 mg once daily) for three months, (2) supervised exercise without atorvastatin, or (3) unsupervised voluntary exercise. Participants who already use statins at the time of recruitment are randomized into two arms: supervised exercise or unsupervised voluntary exercise. The follow-up period extends for 24 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study will assess tumour hypoxia in primary tumours and metastases using EF5-PET imaging, as well as tumour metabolic activity measured by FDG-PET. Additional assessments include circulating biomarkers of hypoxia and metabolism, tolerability of oncological treatments, body composition, physical performance, quality of life, depressive symptoms, nutritional status, cancer-related pain, personal relationships, progression-free survival, and overall survival.\u003c/p\u003e\n\u003cp\u003eThis randomized exploratory study will characterize the tumour-agnostic effects of exercise and metabolic modulation with atorvastatin on tumour hypoxia.\u003c/p\u003e\n\u003cp\u003eResults from the trial will be published in international peer-reviewed journals following study completion, contributing valuable insights into the potential integration of exercise and statin therapy in cancer care.\u003c/p\u003e","manuscriptTitle":"Measuring the oncological value of exercise and statins (MOVES): Changing the tumour microenvironment with exercise and statins — an exploratory pilot trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 01:00:07","doi":"10.21203/rs.3.rs-8501963/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6cd383e5-ec4a-4455-957b-172ed1c9224d","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-29T16:24:37+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-29 01:00:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8501963","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8501963","identity":"rs-8501963","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}