An open, randomised, controlled, parallel, two-arm trial, to assess effectiveness of physical exercise in reducing fatigue in cancer patients undergoing radiotherapy Protocol abstract (proposal):Title: An open, randomised, controlled, parallel, two-arm trial to assess effectiveness of physical exercise in reducing fatigue in cancer patients undergoing radiotherapy. Objective: To assess effectiveness of physical exercise in reducing fatigue in cancer patients undergoing radiotherapy in comparison with the control group (standard care) as a primary objective. Secondary objectives are to measure Quality of Life (QOL) and to assess intervention’s cost effectiveness.Design: This is a multi-centre, randomised, two arm, parallel, controlled study. One arm will receive intervention (physical exercise) and the other arm (control group) will receive standard care. Population: 400 cancer patients aged above 18 years planned to receive radiotherapy.Intervention: Physical aerobic exercise sessions (45 minutes per session) 3 times per week for 8 weeks inside hospital facility under supervision from a physiotherapist.Outcomes: Primary: Fatigue scores (Piper Fatigue Scale (PFS)) at follow up (week 12)Secondary: Fatigue scores (PFS) at baseline, during intervention (week 4) and at the end of the intervention (week 8). Quality of life at baseline, during intervention (week 4), at the end of the intervention (week 8) and at the follow up (week 12). Cost of the intervention.EuroQol-5D-3L and Short Form (SF)-12 will be used to measure QOL in this trial.Statistical analysis:For primary outcome, fatigue mean score difference with 95% confidence interval (CI) at follow up will be calculated between intervention group and the control group.For secondary outcomes, fatigue mean score difference with 95% CI at week 4 and week 8 will be calculated between intervention group and the control group.QOL (EuroQol-5D-3L and SF 12) mean score difference with 95% CI at week 4, week 8 and week 12 will be calculated between intervention group and the control group.Fatigue mean scores and QOL (EuroQol-5D-3L and SF 12) difference with 95% CI between pre-intervention baseline (week 0) and follow will be calculated for each group.Intention to treat (ITT) analysis will be used in the statistical analysis.Background Information:Cancer incidence is increasing in England and the number of the new cases in 2016 were 303,135 excluding non-melanoma skin cancers (Office for National Statistics, 2018).There are different modalities of cancer treatments available including surgery, chemotherapy and radiotherapy. Around 27% of cancer patients receive radiotherapy as part of their treatment regimen (National Cancer Registration and AnalysisService, 2017). One of the most frequent complications related to radiotherapy is the fatigue which is affects most of the patients undergoing radiotherapy. Approximately 77% of the patients who receive radiotherapy show some degree of fatigue (Manir et al. 2012). Cancer-related fatigue is defined as a “persistent, subjective sense of tiredness related to cancer and cancer treatment that interferes with usual functioning” (Mock et al. 2000).There are several methods that can have a role in reducing fatigue during radiotherapy treatments, such as: moderate-intensity aerobic exercise, relaxation activity, cut off caffeine and medications. Some of these methods and strategies to overcome fatigue were suggested by National Health Service (NHS) to reduce fatigue (National Health Service, 2018). A recent systematic review and meta-analysis on the effect of the physical exercise in reducing fatigue during adjuvant radiotherapy for breast cancer patients analysed nine clinical trials with 802 participants showed a statistically significant reduction in fatigue score in the participants in the intervention group compared with the control group ((Standard mean difference (SMD) -0.46, 95% CI -0.79 to -0.14). Quality of life (QOL) was assessed as secondary outcome and the results showed non-significant improvement in QOL in favour of the physical exercise group (SMD 0.46, 95% CI -0.01 to 0.93) (Lipsett et al. 2017).Another systematic review of 19 clinical trials (1686 participants) on the effect of the physical exercise in reducing fatigue in breast cancer patients receiving adjuvant therapy (chemotherapy, radiotherapy or both) showed a significant reduction in fatigue (SMD -0.28, 95% CI -0.41 to -0.16) (Furmaniak, Menig and Markes. 2016).With regard to the other types of cancer, one study also showed a significant reduction in fatigue in prostate cancer patients undergoingradiotherapy with physical exercise group in comparison with the control group (mean difference was -2.06) (Monga et al. 2007).Most of the studies that were conducted to assess the effectiveness of physical excursive were performed on breast cancer patients. Our aim in this trial is to assess effectiveness of the physical exercise on cancer patients undergoing radiotherapy regardless of the cancer type.In addition, most of these studies were conducted outside the UK and our goal is to perform this trial in multiple cancer hospitals inside the UK which may lay the foundation for a new update in the guidelines for fatigue management during radiotherapy. Reducing fatigue in cancer patients can have a beneficial effect on reducing some complications related to fatigue like depression and improving quality of life for these patients.Objectives:Primary: To assess effectiveness of physical exercise in reducing fatigue in cancer patients undergoing radiotherapy in comparison with the control group receiving standard care at the end of the study.Secondary: To evaluate the effectiveness of the physical exercise in improving Quality of Life (QOL) and to assess the intervention’s cost effectiveness.Trial Design:This is an open multi-centre, randomised, controlled, two-arm study to assess the effectiveness of physical exercise in reducing fatigue in cancer patients undergoing radiotherapyThe study will be an open trial. Accordingly, this trial will be considered as a pragmatic trial rather than an explanatory trial.This is a multi-centre trial. Four Cancer hospitals inside the UK were selected to conduct the clinical trial. This study consists of two arms. The first arm is the intervention arm, patients who are planned to do the physical exercise. The other arm is the control arm where the patients will receive standard care.The time from enrolment to end of follow- up will be 12 weeks. The effectiveness of the physical exercise to reduce fatigue and to improve quality of life will be assessed at the end of the follow-up period.Demographic data, including: age, gender and body mass index (BMI) will be taken at the baseline in addition to data on cancer type, fatigue score and QOL score.Table1: Procedures that will be performed during the studyProceduresBaseline (Week 0)During Intervention(Week 4)End of the intervention(Week 8)Follow up(Week 12)Demographic dataX–––Cancer TypeX–––Fatigue score (PFS)XXXXQuality of Life (EuroQol-5D-3L and SF 12)XXXXPhysical Exercise *XXX–* Physical Exercise will be performed three times per week for 8 weeks in the intervention groupEligibility:This trial is an open trial and considered as pragmatic trial, accordingly a wide range of selection criteria will be set which help to increase external validity of the study.Inclusion criteria:- Adults over 18 years with, a cancer diagnosis.- Cancer patients diagnosed with solid tumour.- Patient should be Planned to undergo radiotherapy.- Patient should be able to give written informed consent.Exclusion criteria:- Patients less than 18 years.- Cancer patients diagnosed with haematological malignancies.- Patients planned to undergo chemotherapy or surgery within 12 weeks of starting radiation. Interventions:Aerobic physical exercise is the intervention of choice in this trial. Compared to other types of exercise, aerobic exercise was found to be superior in a systematic review of the effectiveness of physical exercise in improving cancer related fatigue. The study showed that aerobic physical exercise (SMD=1.009, 95% CI 0.222–1.797) has a significantly greater effect than a combination of aerobic and resistance exercises (SMD=0.341, CI 0.129–0.552) (Kessels, Husson, and van der Feltz-Cornelis. 2018).Aerobic exercise is a type of exercise that depends mostly on the aerobic energy-generating process (Plowman and Smith. 2001). Which means that oxygen consumption during this type of exercise will be generated via aerobic metabolism (McArdle, Katch F.I., and Katch V.L 2006). Examples of aerobic exercise are walking, running, swimming, and cycling.In each of the four-cancer hospital, there will be an exercise facility. Patients in the intervention group will be asked to come to the exercise facility three times weekly for 8 weeks during and after radiotherapy treatment which usually lasts between 4 to 8 weeks. Each physical exercise session will last for 45 minutes. A combination of waking, running and cycling will be used under supervision of a physiotherapist. Patients in the control group will follow standard care.Recruitment:As this study is a multi-centre trial, four cancer hospitals in four different areas in the UK will be invited to be involved in the study. Due to the nature of the study, adverse events related to the intervention are not expected, therefore there is no need to have a physician to recruit patients. This can help to reduce cost of the trial. Patient recruitment process will be done by a practice nurse who has access to the patients’ medical records. Study information documents will be sent to the cancer hospital alongside with the invitation letter by post. The trial coordinator will phone call cancer hospitals to invite them to be part of the study and they will be asked to send back their approval to participate in the study. In addition to the practice nurse, cancer hospitals will be asked to assign a physiotherapist who will be responsible to supervise physical exercise of the patients in the intervention group during the study. Study initiation visit will be agreed with each cancer centre. Trial coordinator will ensure that all documents such as study protocol, its appendices are available at the initiation visit. During this visit, trial coordinator will train trial team (practise nurse and physiotherapist) on the study procedures.Through patients’ medical record, potential participants will be identified by the assigned nurse. Eligibility criteria will be assessed to ensure that the potential participant meets the inclusion criteria. This method will increase recruitment rate and eventually will lead to decrease study recruitment period and cost of the trial. Main study information, including aim of the study, intervention nature, benefit and any possible adverse events will be provided to the potential participants through the assigned nurse. After that, they will be asked to sign the consent form before any study procedure.Once the participant agreed to participate on the study and signed consent form. They will be asked to answer and complete baseline questionnaire which include questions about demographic data of the participant, fatigue score and QOL. Some information will be taken directly from the patient medical record such as cancer type. All baseline data will be collected and gathered before randomisation process to avoid recruitment bias.Estimated recruitment period for each cancer hospital will be around four months.This mean that each cancer centre required to recruit around one participant each working day. Since the trial is an open trial with wide eligibility criteria, the sample size of the study can be reach during four months recruitment periods. In addition to that, Face to face recruitment sessions will be used to increase recruitment rate (Treweek et al. 2010). Randomisation and allocation:Once the participants sign the consent form and complete the baseline questionnaire.They will randomly be allocated in a ratio 1:1 to either control or intervention group by using a secure computer system. To avoid subversion bias simple randomisation will be used instead of the stratified randomisation since simple randomisation followed by analysis of covariance is as efficient as restricted randomisation followed by analysis of covariance for sample size more than 50. In addition, telephone randomization system will be used to ensure concealment.Since the trial is open trial, blinding of the participants and the investigator is not possible.This may lead to Hawthorne effects and/or resentful demoralisation.Chances of ascertainment bias is low since the participant will be asked to report the outcome instead of the investigator. The statistician who will analyse the data will be blinded for the allocation sequence of each participant.Chances of delay bias will be also negligible as the period between the randomisation and intervention is short.Trial timelineStudy will last for 12 weeks from the randomisation until the end of the follow up. Once the participants have been randomised either to the intervention group or to the control group, the participants on the intervention group will be asked to attend physical exercise sessions until the week 8 of the study. Physical exercise session will be held at the exercise hospital facility and will last for 45 minutes. It will be repeated three times weekly.Follow up evaluation will be done at the week 8 and week 12 of the study. Main outcome will be measured at the end of the study.Sample size calculation:Sample size estimation is based on the results of the previous studies that were conducted to assess effectiveness of the physical exercise in reducing fatigue in patients undergoing radiotherapy.The results of these systematic reviews are showed in the table 2.Table2: Standard mean difference and 95% CI of the systematic reviews:Systematic reviewNumber of trialsNumber of participantsSMD95% CILipsett et all. 20179802-0.46-0.79 to -0.14).Furmaniaket et al.201619 1686-0.28-0.41 to -0.16Keseles et al. 201821701.010.22 to 1.80Each systematic review assessed fatigue reduction in different measurement unit. Accordingly, standard mean difference of these systematic review will be used to calculate sample size.SMD for combined systematic review was around 0.5, however the number of trials is higher in Furmaniaket et al.2016 study which showed that the SMD is around 0.28. Accordingly, for our trial Standard reference (d) will be assumed to be 0.30. Another point that supports considering standard reference 0.30 instead of 0.5 that the systematic review and meta-analysis will mostly over-estimate effect sizes because of the publication bias where most of the researchers publish positive outcome results (Torgerson and Torgerson 2008).To calculate the sample size, the following equation described by Lehr (1992) which calculate sample size of continuous outcome was used_N= 32/ d2 N: sample size, d: standard differenceN= 32/(0.3)2N= 356 participantsAttrition rate is varied between previous studies. Table 3 explore attrition rate of different previous trials.Table 3: Attrition rate of previous trialsStudyDrop-outNumber of participantsAttrition rate %Chandwani et all. 2014141638.6%Chandwani et al. 20103614.9%Mutrie et all. 20072920314.3%Drouen et al. 20052238.7%Average attrition rate in the previous studies was around 10%. Accordingly, for this trial attrition rate will be assumed to be 10%.Attrition factor = 1/ (1-0.1) = 1.11 N = 1.11 * 356 = 394For this trial to detect a difference of 0.30 in effect size, 394 participants are required (i.e., 197 in each group) to have an 80% power to show the difference with a significant level of 5%, taking into considerations 10% expected dropout.Number of subjects will be rounded to 400 subjects. Each cancer hospital will be asked to recruit 100 patients. Compliance and adherence:Adherence to the study is measured in the previous studies and the detailed results is shown in the table 4: Table 4: Adherence rate:StudyAdherence rate %Chandwani et all. 201486%Mutrie et all. 200770 %Drouen et al. 200283.4%Data Collection:Baseline data will be collected from all participants before randomisation throughout a questionnaire. Baseline questionnaire will include questions about demographic data of the participants, type of cancer, fatigue score and QOL.During the study at week 4, at the end of the physical exercise sessions at week 8 and at the follow up visit (end of the study), all participant will be asked to answer questions to measure the primary and secondary outcomes through a questionnaire.Outcome:Primary:Fatigue scores (Piper Fatigue Scale (PFS)) at the end of the study (week 12) will be measured and the difference in the mean PFS score between intervention and control group will be assessed.PFS scale is composed of 22 numerically scaled, 0 to 10 items that measure four dimensions of subjective fatigue: behavioural/severity (6 items), affective meaning (5 items), sensory (5 items), and cognitive/mood (6 items). To calculate the total fatigue score, 22-item scores will be added together and will be divided by number of items (22). The resulted score will be on a numerical score of 0 to 10. (Piper et al. 1998).PFS score at the end of the study is chosen to be the primary outcome to assess if the intervention effect in reducing fatigue will last after the end of the physical exercise sessions.Secondary:-PFS during the study at week 4 will be measured and the difference in the mean PFS score between intervention and control group will be assessed.-PFS at the end of the physical exercise sessions at week 8 will be measured and the difference in the mean PFS score between intervention and control group will be assessed.-PFS at the baseline and at the end of the study will be measured and differences in the PFS score between them for each group will be assessed. -QOL at the end of the study will be measured and the difference in the mean QOL between intervention and control group will be assessed.-QOL during the study at week 4 will be measured and the difference in the mean QOL between intervention and control group will be assessed.-QOL at the end of the physical exercise sessions will be measured and the difference in the mean QOL between intervention and control group will be assessed.-QOL at the baseline and at the end of the study will be measured and differences in the QOL between them for each group will be assessed. -Cost of the intervention (physical exercise).EuroQol-5D-3L and SF 12 will be used to measure QOL in this trial.EuroQol-5D-3L consists of 2 pages the first one is the EQ-5D descriptive system and the second one is EQ visual analogue scale (EQ VAS). The EQ-5D-3L descriptive system includes five items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of these items has 3 levels: no problems, some problems, and extreme problems. The EQ VAS is a vertical visual analogue scale where the participants reported their health state in a scale of 1 to 10. (EQ_5D, 2017).The SF-12 is a short form questionnaire with 12 questions. These questions cover two domains of mental and physical (Melville et al. 2003).Statistical Analysis:Intention to treat (ITT) will be used for the analysis since it is the best way for data analysis of clinical randomised trials (Hollis and Campbell, 1999). If there is any cross-over of participants into other arm, the participants should remain in their original arm during analysis as if we move them to the other arm, this will lead to serious bias and will increase chance of type 1 error (Torgerson and Torgerson 2008).ITT can lead to increase chance of dilution bias. To decrease dilution bias, attrition rate during the study should be controlled. Based on the results of the previous studies attrition rate was low (around 10%). To keep attrition rate in the study as low as possible, participants will be encouraged to remain in the trial. In addition, participants who want to leave the study will be asked to complete questionnaire at follow up.SAS statistical package version 9.4 or higher will be used for evaluating primary and secondary outcomes in the study.Primary outcome analysis:PFS mean differences with 95% confidence interval (CI) at follow up will be calculated between intervention group and the control group using independent t-test.Secondary outcome analysis:PFS, EuroQol-5D-3L and SF 12 mean differences with 95% CI at week 4 and week 8 will be calculated between intervention group and the control group using independent t-test.EuroQol-5D-3L and SF 12 mean difference with 95% CI at the end of the study will be calculated between intervention group and the control group using independent t-test.PFS, EuroQol-5D-3L and SF 12 mean differences with 95% CI at the baseline and at the end of the study will be measured and differences in the mean score between these periods them will be assessed using paired t-test.Ethical consideration:Ethical approval from the ethics committees will be asked before start of the trial for all cancer centres planned to be part of the study.Consent form:The practice nurse will explain verbally to all subjects, in easily understood terms, the nature and objectives of the study, any possible adverse events, study timeline, as well as the possibility of voluntary withdrawal from the study (at any time they wish) without this affecting their standard care and treatment.The participants will have the opportunity to ask questions concerning the study and will be allowed adequate time to decide on voluntary participation. Participants will be allowed to read the written consent form, and then they will be asked to sign it prior to the randomisation process.Confidentiality and Data protection:Participant data from the study will be kept in a secured place for at least 5 years in accordance with the Data Protection Act (Data Protection Act, 2018). Softcopy data of the study will be kept in a strictly secured computers. And only authorised persons will have access to these data. Economical evaluation:Economical evaluation of the intervention will be assessed by using Cost utility analysis. By obtaining quality of life outcomes during the study, quality-adjusted life years (QALYS) can be estimated. Cost effectiveness of any intervention is based on the incremental costs and benefits and this is expressed in Incremental cost-effectiveness ratio.Cost of the trial:The following costs are expected during the trial:-Cost of employment for the research team which include: trial coordinator, practice nurses, physiotherapists, statistician, data management employee and health economist.-Cost of using exercise facility and other facilities in the cancer centres.-Cost of the study visits including transportation.-Cost of the study documents, questionnaires, consent forms and other documents.-Cost of the practice nurse time and physiotherapist time.-Cost of the software program used for randomisation and allocation process alongside data entry process.References:Chandwani, K.D. et al. (2014). Randomized, controlled trial of yoga in women with breast cancer undergoing radiotherapy. Journal of Clinical Oncology, 32(10),1058-1065.Chandwani, K.D. et al. (2010). 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