Article Reference
Kampshoff, C. S., Chinapaw, M. J., Brug, J., Twisk, J. W., Schep, G., Nijziel, M. R., … Buffart, L. M. (2015). Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study. BMC Medicine, 13(1). doi:10.1186/s12916-015-0513-2
Secondary References
BURNHAM, T. R., & WILCOX, A. (2002). Effects of exercise on physiological and psychological variables in cancer survivors. Medicine & Science in Sports & Exercise, 34(12), 1863-1867. doi:10.1097/00005768-200212000-00001
Gibbs Z. (2015). Exercise for breast cancer patients with lymphedema. Australian New Zealand Clinical Trials Registry. 2012. ACTRN12612000256875
Introduction: Individuals being treated for cancer often experience the effects of deconditioning which include fatigue, loss of strength, motivation, quality of life, and function. Exercise is a safe intervention which has the ability to ameliorate these side effects. Given the positive outcomes, exercise has been endorsed by international evidence based guidelines as a standard of care for cancer survivors. A limitation to these guidelines is the exercise prescriptions remain relatively generic. Optimal amounts of volume, intensity, and frequency remain to be discovered. Surprisingly, there have been only two randomized control trials to date exploring exercise intensity after completion of primary cancer treatments. The results of these trials being mixed. Burnham (2002) found both moderate and low intensity aerobic exercise improved cardiorespiratory fitness while Gibbs (2015) noted high intensity resistance exercise improved cardiorespiratory fitness to a greater degree than low intensity. With the relatively small amount of literature on the topic, it is imperative more research is conducted on the effects of exercise intensity on health parameters in this population. Therefore, the purpose of this study is to examine the effectiveness of high intensity (HI) and low to moderate intensity (LMI) resistance training and endurance exercise in comparison to a control group in cancer survivors. The primary outcomes are cardiorespiratory fitness, muscle strength, and fatigue as primary outcomes. Secondary outcomes include included HRQoL, physical activity, daily functioning, body composition, mood, and sleep disturbances as secondary outcomes.
Purpose: The purpose of this study is to examine the effectiveness of high intensity (HI) and low to moderate intensity (LMI) resistance training and endurance exercise in comparison to a control group in cancer survivors
Procedures and Methods:
Design: This study was designed using three arms. There was a high intensity (HI), low to moderate intensity (LMI), and a control (WLC). This design appears ideal given the authors outlined goals above. The three arms of the study allow the researchers to pit high and low intensity against each other, and then also examine both against a control group. Given the study has three arms; the number of participants will have to be larger in order to provide sufficient power. The study spanned across multiple hospitals and obtained IRB approval across all locations, ensuring appropriate ethics.
Patient Selection: The authors included individuals’ ≥18 years that had breast, colon, ovarian, cervix or testis cancer, or lymphomas with no indication of recurrent or progressive disease. Subjects also had had completed chemotherapy. The exclusion criteria were not being able to perform basic activities of daily living, cognitive disorders or severe emotional instability, other serious diseases that might hamper patients’ capacity of carrying out HI exercise, and inability to understand the Dutch language.
Examining the exclusion criteria there are a few things to note. It appears the subjects had relatively limited comorbidities. In other words, the population was relatively healthy other than having previously undergone treatment for cancer. This puts into perspective the results of this study, as they are limited in scope. Cardiovascular disease is a common disease and results in a significant amount of mortality in this population. It is understandable why the authors would want to exclude these kind of issues, given the nature of the exercise. One possibility would be to have the patients cleared by a cardiologist to participate in HI exercise, which would increase the ability to generalize the results.
Randomization: Randomization occurred via an independent research assistant using a table of random numbers generated from statistical software. The assessments were performed by blinded assessors. Overall, this was a good approach to randomization. I have no issues with this process.
Exercise Intervention: The exercise intervention consisted of a combination of resistance training and aerobic exercise. The exercise prescriptions were identical with the exception of training intensity. The resistance training protocol contained six exercises of two sets of 10 repetitions. The HI group exercised at an intensity beginning at 70% repetition maximum and increased to 85% repetition maximum by week 12. The LMI group started at an intensity of 40% repetition maximum and increased to 55% of repetition maximum. The workload was adjusted by a physiotherapist every 4 weeks via an indirect 5 repetition maximum test. The aerobic training consisted of interval exercises. The first four weeks patients cycled 2×8 minutes with alternating workloads. Workload was determined by a steep ramp test. The HI group cycled 30 seconds at a workload of 65% and 60 seconds at 30% intensity. The LMI group cycled 30 seconds at a workload of 65% and 60 seconds at 30% intensity. After 4 weeks, the 60 second block was reduced to 30 seconds. Workload was again adjusted accordingly via a physiotherapist and retesting every 4 weeks. At week 5, an additional endurance session was substituted for the second 8 minute block. This session consisted of 3 x 5 minutes cycling at constant workloads, with 1 minute rest between bouts. The sessions were performed on a cycle ergometer or treadmill. The workload was determined via heart rate reserve (HRR) using the Karvonen formula. The HI group training at a minimum of 80% intensity. The LI trained at 40-50% intensity. All sessions were closely monitored by a physiotherapist.
The exercise intervention description was adequate. The first detail I noticed missing was the rest periods between resistance training sets. It could be conceived higher intensity exercises were harder, and individuals required more rest between bouts, resulting in less of a cardiorespiratory challenge. The lower intensity group may have felt recovered earlier, and therefore challenged the cardiorespiratory system to a greater degree. Standardizing the rest periods would also enable the study to be recreated or the protocol to be followed exactly in future investigations.
Measurements: Measurements were assessed at baseline, 4-6 weeks, and after 12 weeks. Cardiorespiratory fitness was measured using peak oxygen uptake during a ramp protocol on a cycle ergometer. Expired gases were collected and analyzed to determine peak VO2, which was defined as the highest values of oxygen averaged over a period of 15 seconds within the last minute of exercise. During this period peak power was also calculated in Watts. Upper body strength was measured with a JAMAR hand grip dynamometer. The mean of three attempts was recorded using the dominant hand. Lower body function was assessed via a 30 second chair-stand test. Subjects performed sit to stands as quickly as possible for seconds and the number was recorded. Both these tests have been proven valid in the literature as appropriate means to determine upper body strength and lower body function. Fatigue was evaluated using the Multidimensional Fatigue Inventory (MFI). This questionnaire is validated and consists of 20 questions divided into subscales which include general fatigue, physical fatigue, motivation, and mental fatigue.
Secondary measurements included health related quality of life (HRQoL) using the following: the European Organization Research and Treatment of Cancer-Quality of Life questionnaire-Core, anxiety and depression by the Hospital Anxiety and Depression Scale, sleep disturbances with the Pittsburgh Sleep Quality Index, participation in daily life using the Impact on Participation and Autonomy, the Physical Activity Scale for the Elderly questionnaire. To objectively measure physical activity, a wearable accelerometer was used for seven consecutive days. Bodyweight (nearest 0.1 kg), height (nearest 0.1 cm), BMI, and body fat using four skin-fold measurements (mm) were also recorded.
Calculation of Sample Size: Power calculations were based on a previously uncontrolled trial assessing HI in 119 cancer survivors. To detect a difference in peak VO2 of 3 mL/min/kg (SD=5.8), with a power of 0.80 and two-sided alpha of 0.05, 60 participants were required. Attrition rate was estimated at 20-40%, an estimated sample size of 280 was required.
The authors did an extensive job explaining their methods for justifying the trial size. They used a previous study to base their assumptions and estimated statistical equations. Overall, this was a quality section with good detail and justification.
Results: 74% of the HI and 70% of the LI attended more than 80% of the sessions (P = 0.53). Both groups demonstrated statistically greater improvements in peak VO2 compared to the control. HI (β = 2.2; 95 % CI, 1.2–3.1) improved to a greater extent than LMI in peak VO2 and LMI (β = 1.3; 95 % CI, 0.3–2.3), but the difference was not statistically significant (p=0.08). No differences were found for grip strength or 30 second chair-stand test. Both interventions significantly reduced general and physical fatigue with no differences between groups. HI improved quality of life (β = 5.9; 95 % CI, 2.0–9.8) and anxiety (β = −1.0; 95 % CI, −1.7 to −0.3, both groups improved in physical function (HI: β = 3.1; 95 % CI, 0.7–5.5 and LMI: β = 4.1; 95 % CI, 1.6–6.6), and less work related problems were demonstrated in the LMI group (β = −0.3; 95 % CI, −0.6 to −0.02).
Discussion: This study demonstrated 12 weeks of HI and LMI were effective in improving peak VO2, quality of life, and physical function in subjects whom completed cancer treatment. The results from this study are consistent with previous research on HI and LMI. The mean peak VO2 improvements of 4.4 mL/kg/min after HI and 3.3 mL/kg/min after LMI are similar to previous research in cancer survivors. It is important to note, the HI group experienced larger nearly significant gains in peak VO2. Improving peak VO2 is important in cancer survivors, as research has demonstrated their peak VO2 levels are very poor compared to healthy adults. Future research should focus on confirming this theory. In general, exercise improved measures of fatigue and physical function. This is important as fatigue often prevents or limits cancer survivors from participating in physical activity. Increased levels of physical activity are associated with reduced cancer recurrence. Both groups failed to improve in levels of strength and lower extremity function. This may be due to poor measurement choice, which failed to identify clinically significant improvements in body strength. The LMI group also experienced less work related problems, which may indicate a stress reducing element in LMI compared to HI. In conclusion, both HI and LMI were effective in producing significant gains in peak VO2 and measures of fatigue in cancer survivors. HI can safely be implemented as a method to improve peak VO2 in cancer survivors. Additionally, HI may be preferred over LMI, as this study revealed a dose-response relationship for peak VO2.
My Thoughts: This research study had many strengths and I thought it was really well done. First, the study was a large multi-center RCT which reduces the risk for bias. The sample size was large, which reduces the risk for sampling and type II error. Second, the authors did an excellent job describing their methods. The description would allow the study to be replicated with the minor exception of not adding the rest breaks during the resistance training session. They also did an excellent job describing their methods to calculate sample size and pre-trial power analysis. Third, they generated appropriate conclusions without overly exaggerating the results. The HI and LMI were not significantly different, but it was close and the authors made this clear. They suggested future research should look to clarify whether HI does improve peak VO2 more so than LMI. Overall, I thought this research was very professional. I hope to be able to complete a study of this quality in the future.
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