Physical Training and Cancer-a Multicenter Clinical Trial

Study Overview
=================
Brief Summary
-----------------
Excessive tiredness (fatigue) is a common problem in cancer patients and can affect quality of life negatively. There is limited knowledge about the physical mechanisms that cause fatigue, and there is no medical treatment. Physical activity can reduce the inconvenience, but the investigators need to learn more about the type and intensity of exercise that works the best as well as how to motivate patients to exercise. The overall aim, is to evaluate the efficacy and cost-effectiveness of individually tailored high (H) and low/medium (LM) intensity physical training, with or without behavioural medicine (BM) support strategies, during adjuvant oncological treatment on; Cancer Related Fatigue (CRF),Quality of Life (QoL), mood disturbance, adherence to the cancer treatment, adverse effects, disease outcome, return to a daily life after completed treatment and return to work. The investigators will also describe changes in inflammatory markers and cytokines related to physical training and gene expressions following training to investigate whether these serve as mediators for the effects of physical training on CRF and QoL. This will be evaluated in newly diagnosed breast, colorectal and prostate cancer patients during adjuvant therapy at three different centres in Sweden; Uppsala, Lund/Malmö and Linköping. A 2x2 factorial design will be used, 600 patients will be randomised to H, H+BM, LM or LM+BM. Patients will train two times per week during 6 months. This project will give; new knowledge about aspects for individuals to gain improved well-being and quality of life, facilitated return to work, and possibly reduced risk of cancer recurrence. This in turn would result in lower burden on the health care system, reduced societal costs and have a positive impact on public health. Implementation of the results into clinical practice will be facilitated by the close collaboration between researchers and clinicians, and the fact that the study is performed in clinical settings.

Detailed Description
-----------------
Purpose and Aims The main aim is to determine the effects of high or low intensity physical training with or without integrated behavioral medicine support strategies to prevent and minimize cancer related fatigue (CRF), improve health related quality of life (QoL) and to understand the role of inflammation and cytokines in the development and maintenance of CRF, as well as to increase knowledge with respect to cost-effectiveness of rehabilitation programs. This will be evaluated in newly diagnosed breast, colorectal and prostate cancer patients during adjuvant therapy at three different centers in Sweden; Uppsala, Lund/Malmö and Linköping and one in Norway. More specifically, the investigators' objectives are to: Investigate the effects of high intensity training compared to low intensity training on patient reported outcomes (CRF as primary endpoint), chemotherapy/radiation completion rates, medical (oncology) adverse effects, physical activity and daily function, during adjuvant treatment and at long-term-follow up. In addition, effects on the course of disease (e.g time to relapse). Investigate if supplemental behavioural medicine support strategies increase adherence to exercise during adjuvant therapy and further if they increase the maintenance of physical activity behaviours and decrease sedentary time in the long run. Explore the role of changes in inflammatory markers and cytokines related to physical training and following training to investigate whether these serve as mediators for the effects of physical training on CRF and QoL. Pursue the investigation of a direct role of cytokines secreted from the working muscles, in inhibiting cancer cell growth and inducing apoptosis. Evaluate health economic issues; cost effectiveness of the interventions, health production and individual wellbeing. In Phys-Can, the investigators will implement rigorously designed and adequately powered randomized longitudinal multicenter clinical trials, with physical training and behavioral medicine support interventions. The highly multi- and interdisciplinary and international consortium behind this proposal is in an excellent position to perform international and interdisciplinary competence- and network-building activities to generate valid, high quality data covering all areas included in the project, from basic biomedical data to patient reported outcomes (PROs), i.e. from bench to bedside. This is unique in health care sciences. Study design A 2x2 factorial design will be used. With this design the investigators can study main effects and interactions between factors (groups). Patients will be randomized to one of the following groups; A) individually tailored high intensity training twice a week with (H+BM) or without behavioral medicine support strategies (H) or B) individually tailored low intensity training twice a week with (L+BM) or without behavioral medicine support strategies (L). Study sample/procedure Patients, who are recently diagnosed with breast cancer, colorectal cancer or prostate cancer and scheduled for adjuvant therapy at Uppsala, Lund/Malmö, Linköping and Haukeland University hospitals will be consecutively included in the study. Based on the power calculation, 612 patients will be included. All patients will exercise twice a week during 6 months which is equal to the most extensive adjuvant treatment period. It is also an optimal period to achieve physical training effects and to establish physical activity behavior. Physical training under the guidance of trained coaches will be offered twice a week. Training intensity is 40-50% (low intensity group) or 80-90% (high intensity group) of maximal cardiorespiratory fitness/muscular strength. Physical training sessions consist of both cardiorespiratory and resistance exercise. Every four week, progress from resistance training is evaluated by means of a strength test, and absolute intensity is adjusted accordingly Motivational and self-regulatory behavioral medicine support strategies (motivational and self-regulatory strategies) will be provided for the H+BM and the L+BM groups i.e. strategies to enhance engagement in the high and low intensity exercise programs respectively, and to maintain health enhancing physical activity after the completion of the programs.

Official Title
-----------------
Physical Training and Cancer- Effects and Understanding of Mechanisms for Prevent and Minimizing Cancer Related Fatigue, Improve Quality of Life and Disease Outcome

Conditions
-----------------
Breast Cancer, Colorectal Cancer, Prostate Cancer

Intervention / Treatment
-----------------
* Behavioral: high intensity exercise
* Behavioral: low/medium intensity exercise
* Behavioral: Behavioral medicine strategies


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: understand and talk Swedish. patients with breast cancer who receive neoadjuvant / adjuvant chemotherapy and / or adjuvant radiotherapy and / or adjuvant endocrine treatment. patients with colorectal cancer who receive adjuvant chemotherapy. patients with prostate cancer who receive neoadjuvant / adjuvant endocrine treatment with the addition of curative radiation therapy. Exclusion Criteria: Patients unable to perform basic activities of daily living. Patients with cognitive disorders such as dementia and severe psychiatric illness. Patients with disabilities that may prevent physical activity: (eg, unstable angina, heart failure, chronic obstructive pulmonary disease, orthopedic and neurological diseases). Breast cancer stage IIIb. Undergoing treatment for other types of malignant disease.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High intensity<br>high intensity exercise 80-90% | Behavioral: high intensity exercise<br>* high intensity exercise 80-90%<br>|
| Experimental: Low/Medium intensity<br>low/medium intensity exercise 40-50% | Behavioral: low/medium intensity exercise<br>* low/medium intensity exercise 40-50%<br>|
| Experimental: High Intensity with BM<br>high intensity exercise with Behavioral medicine strategies¨ 80-90% | Behavioral: high intensity exercise<br>* high intensity exercise 80-90%<br>Behavioral: Behavioral medicine strategies<br>* Motivational and self-regulatory behavioral medicine support strategies<br>|
| Experimental: Low/Medium intensity with BM<br>low/medium intensity exercise with Behavioral medicine strategies 40-50% | Behavioral: low/medium intensity exercise<br>* low/medium intensity exercise 40-50%<br>Behavioral: Behavioral medicine strategies<br>* Motivational and self-regulatory behavioral medicine support strategies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Fatigue | Multi Dimensional Fatigue Inventory (MFI), | post oncol treatment (expected time frame 6-8 weeks), 6 month, 1,2,5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Quality of Life | The European Organisation for Research and Treatment of Cancer (EORTC)EORTC-QLQ30 | post oncol treatment (expected time frame 6-8 weeks), 6 month, 1,2,5 years | 
| Change in Mood disturbance | Hospital Anxiety and Depression Scale- (HADs) | post oncol treatment (expected time frame 6-8 weeks), 6 month, 1,2,5 years | 
| Change in Function in Daily life | WHO Disability Assessment Schedule | 6 months,1, 2, 5 years | 
| Change in pain | Brief Pain Inventory | post oncol treatment (expected time frame 6-8 weeks), 6 month, 1,2,5 years | 
| Change in Cardio respiratory fitness | maximal oxygen uptake (VO2 max test) | 6 month | 
| Change in Muscle strength | One Repetition Maximum Lower extremities: One Repetition Maximum (leg press) | 6 months | 
| Health Economy | Euroqol- (EQ5D) | 12 months | 
| Cancer recurrence | number of patients with recurrence | 10 year | 
| Sleep | Insomnia severe index | 6 months | 
| Health Economy register | register data | 12 months | 
| Cancer recurrence | Medical records | 6 months, 1, 2, 5, 10 years | 
| Treatment completion rate | Medical records | 1, 2, 5, 10 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Breast cancer, prostate cancer, colorectal cancer, fatigue, physical exercise, randomised trial, intervention