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 interventions 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 interventions 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 radiotherapy
The 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 study
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* Physical Exercise will be performed three times per week for 8 weeks in the intervention group
Eligibility:
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 0.2221.797) has a significantly greater effect than a combination of aerobic and resistance exercises (SMD=0.341, CI 0.1290.552) (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 timeline
Study 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:
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Lipsett et all. 2017
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