Measuring Oncological Value of Exercise and Statin

Study Overview
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Brief Summary
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The aim of the study is to find out whether supervised physical exercise during cancer drug treatment improves the effectiveness of the treatment in metastasized breast, kidney, ovarian and prostate cancer compared to unsupervised exercise. In addition, the investigators are investigating whether the use of atorvastatin combined with guided group exercise training would further improve the response to cancer treatment.

Detailed Description
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Despite the marked differences between different malignancies' genetic, metabolic, and prognostic factors, hypoxia and adaptation of metabolic changes favoring hypoxic microenvironment are common factors in most solid tumors. Hypoxic microenvironment provides cancer cells multiple advantages: protection from immune system, somatic mutations leading to more aggressive form of cancer, and cancer cells that are adjusted to hypoxic conditions are more prone to form metastases. One possible mechanism for cancer cell to adjust to hypoxic microenvironment is related to lipid metabolism; lipids are known to accumulate into cancer cells in many cancer types. One of the most promising ways to reduce hypoxia in solid tumors is to increase physical exercise. Furthermore, tumors' lipid metabolism can be affected by treatment with cholesterol-lowering statins, which decreases serum cholesterol levels and inhibits cancer cells' own lipid synthesis. The aim of this randomized clinical trial is to investigate if supervised group exercise will improve response to cancer drug treatment in metastasized breast, kidney, prostate, and ovarian cancer compared to unsupervised exercise. The investigators will also evaluate if atorvastatin treatment in combination with guided group exercise can promote even better treatment responses than exercise alone. Exercise program includes aerobic and resistance training. This study is a randomized phase III pilot study testing the research hypothesis for the first time in humans. In the pilot phase of the study, a total of 240 cancer patients (n=60/cancer type) will be recruited into the study and randomized 1:1:1 into three different groups, i.e. 20 people in each group from each cancer type: 3 months of supervised group exercise 3 months of supervised group exercise and at the same time atorvastatin 40 mg/day to a control group that exercises voluntarily without guidance Before the study begins, the patients are informed orally and in writing about the study. The patients who agree to participate in the study sign an informed consent. The patient follow-up time in each group is two years in 3 months intervals (first visit and 8 follow-up visits) in conjunction with standard cancer treatment follow-up visits. Blood and urine samples and questionnaire data are collected at baseline and at each follow-up visit. Body composition and physical performance are measured at baseline and twice after the intervention. Patients QoL and experiences of exercise are measured in qualitative interviews (in the group participating the qualitative sub-study). The main response variables are cancer progression during cancer treatment based on imaging, symptoms or laboratory findings and mortality of the patients. The other variables of interest in this study are: whether exercise alone reduces hypoxia sufficiently to improve the effectiveness of cancer chemotherapy, and whether inhibiting lipid synthesis with a statin enhances this effect. to evaluate the patient's experiences of cancer drug treatment, their side effects and the effects of increasing exercise on the patient's perceived quality of life, perceived pain, depressive symptoms, nutrition and relationships. Adverse events from cancer treatment and treatment interruptions are also monitored.

Official Title
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Syöpäpotilaan Ennusteen Parantaminen Muuttamalla syövän mikroympäristöä ja Metaboliaa Liikunnalla ja lääkkeellisesti - Measuring Oncological Value of Exercise and Statin

Conditions
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Breast Cancer, Prostate Cancer, Kidney Cancer, Ovarian Cancer, Metastatic Breast Cancer, Metastatic Kidney Cancer, Metastatic Renal Cell Carcinoma, Metastatic Renal Cancer, Metastatic Prostate Cancer, Metastatic Prostate Adenocarcinoma, Metastatic Ovarian Cancer, Metastatic Ovary Cancer

Intervention / Treatment
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* Behavioral: Guided physical exercise
* Drug: Atorvastatin
* Other: Independent exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient has metastatic prostate cancer, breast cancer, ovarian cancer or kidney cancer confirmed histologically and by imaging, for which 1st-line cancer drug treatment is started Prostate cancer: First course of docetaxel treatment for metastatic prostate cancer. Breast cancer: First-line medical treatment of metastatic breast cancer regardless of hormone receptor status. Kidney cancer: medium-risk/high-risk kidney cancer according to the IMDC classification, for which 1st-line cancer drug treatment is started as tki monotherapy or as a combination treatment that includes tki medication. - the randomization of subjects is stratified according to gender Ovarian cancer: stage III or IV cancer for which 1st-line chemotherapy treatment is started. The patient agrees to the study and signs a written informed consent. Adult (18 years=>) women (breast, ovarian and kidney cancer) and men (prostate and kidney cancer) are recruited for the study. In women, the use of a reliable contraceptive during the intervention Exclusion Criteria: High risk of bone fractures Inability to physical exertion and/or unsuitability for cancer drug treatment Poor co-operation ability for psychological reasons Active use of cholesterol-lowering drugs Severe liver or kidney failure Troublesome side effects that occurred in the past during cholesterol medication Continuous use of medicinal substances that interact with atorvastatin during the study period A special group of subjects according to the Medical Research Act (1999/488) (e.g. minors and pregnant or lactating women)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The patients are randomized equally into three groups: 1/3 into guided exercise group, 1/3 into guided exercise and statin-treatment group and 1/3 into non-guided exercise group
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Guided physical exercise arm<br>20 patients from each type of cancer (altogether 80) are randomized to a 3 months guided physical exercise arm. At the beginning of the intervention the patients' physical condition and body composition are measured. After that an exercise program begins. All subjects participate in physical exercise program twice a week for three months. At the end of the intervention, the physical condition and body composition are measured again. During the follow-up after the intervention the patients are advised to exercise regularly. Physical condition and body composition are measured again after 6 months. Exercise activity is asked during each follow-up visit. | Behavioral: Guided physical exercise<br>* Patients will be participating in guided physical exercise program regularly two times / week at a sports facility and guided by a professional trainer. They will participate in aerobic and resistance exercises during the sessions.<br>|
| Experimental: Atorvastatin arm<br>20 patients from each type of cancer (altogether 80) are randomized to a 3 months guided physical exercise + atorvastatin (40 mg QD) arm. At the beginning of the intervention the patients' physical condition and body composition are measured. After that an exercise program begins. All subjects participate in physical exercise program twice a week for three months. At the end of the intervention, the physical condition and body composition are measured again. During the follow-up after the intervention the patients are advised to exercise regularly. Physical condition and body composition are measured again after 6 months. Exercise activity is asked during each follow-up visit. | Behavioral: Guided physical exercise<br>* Patients will be participating in guided physical exercise program regularly two times / week at a sports facility and guided by a professional trainer. They will participate in aerobic and resistance exercises during the sessions.<br>Drug: Atorvastatin<br>* Patients will be participating in guided physical exercise program regularly two times / week at a sports facility and guided by a professional trainer. They will participate in aerobic and resistance exercises during the sessions. In addition to the exercise program they will be given atorvastatin 40 mg QD medication.<br>|
| Active Comparator: Non-guided physical exercise arm<br>20 patients from each type of cancer (altogether 80) are randomized to a non-guided physical exercise arm. The patients' physical condition and body composition are measured at baseline. The control group is advised of the benefits of physical exercise and they get an exercise program to follow. Participants in the control group exercise on their own. The physical condition and body composition of this group is also measured at three months and six months after baseline to detect changes. After that the patients are given advise to exercise regularly and this is asked during each follow-up visit. | Other: Independent exercise<br>* The control group is advised of the benefits of physical exercise and they get an exercise program to follow. Participants in the control group exercise on their own.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to cancer progression | Radiological progression • Radiological progression of the disease according to RECIST criteria (version 1.1.) compared to the situation at the start of cancer treatment in all cancer types. If the cancer treatment includes the use of immune checkpoint inhibitors, the imRECIST criteria are applied to evaluate the response In addition, the disease is considered advanced if both of the criteria below are met: Biochemical progression: PSA progression in prostate cancer, (three consecutive PSA increases measured at least one week apart, two > 50% increases from the lowest PSA level and PSA > 2 ng/ml) with testosterone at castration level (< 50 ng/ml or 1.7 nmol/l) Ca15-3 marker increase in breast cancer (three consecutive marker increases that the clinician considers significant) In ovarian cancer, ca12-5 marker increase (three consecutive marker increases that the clinician considers significant) Clinical progression o ECOG 3 or less (long-term) | From randomization until the date of first documented progression, assessed at twelve week intervals up to 24 months | 
| Mortality | Time to death from the beginning of the first-line medication | From randomization until the date of death, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hypoxia markers in serum (VEGF, HIF1-alpha, carboanhydrase IX, LADH) | Hypoxia markers in the serum | At baseline and at 3 months | 
| Tolerability of treatment | Incidence of grade 3 or worse adverse events during cancer treatment | From date of randomization, assessed at twelve week intervals up to 24 months | 
| Fat/muscle ratio as measured with impedance test | Body composition measurement before and after the intervention | At baseline and at 3 and 6 months | 
| Physical performance with standardized muscle strength tests | Muscle strength tested with three standardized tests (squat test, core dynamic strength test, biceps flexion test) before and after the intervention. | At baseline and at 3 and 6 months | 
| Changes in tissue hypoxia | The amount of hypoxia in cancer foci determined by PET-CT scan using specific hypoxia-sensitive tracers in a sub-study | At baseline and at 3 months | 
| Changes in quality of life | EORTC-QLQ-C30 questionnaire to measure quality of life, score from 0 to 100. A high scale score for a functional scale represents a higher level of functioning, a high score for a symptom scale represents higher level of symptoms. | At baseline and at 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months and 24 months | 
| Depressive symptoms | Patient Health Questionnaire (PHQ-9), score from 0 (no depression) to 27 (severe depression). | At baseline and at 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months and 24 months | 
| Severity of pain | The severity of pain and its impact on functioning. Brief Pain Inventory questionnaire including 9 items. Pain severity scale from 0 (no pain) to 10 (worst pain), pain interference from 0 (does not interfere) to 10 (completely interferes). | At baseline and at 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months and 24 months | 
| Nutritional status | Mini Nutritional Assessment (MNA) questionnaire. A score of 7 or less (malnutrition) to 24-30 (normal nutrition). | At baseline and at 3 months, 6 months, 9 months, 12 months, 15 months, 18 months, 21 months and 24 months | 
| Relationship satisfaction | The relationship questionnaire consists of two previously used, validated measures: Dyadic Adjustment Scale (DAS) and Marital Communication Inventory. | At baseline and at three months, twelve months and 24 moths. |