2015), A framework for prescription in exercise-oncology research. Journal of Cachexia, Sarcopenia and Muscle, 6, 115–124. doi: 10.1002/jcsm.12042., , , , , and (
The field of ‘Exercise-Oncology’ has burgeoned dramatically in scope and impact since publication of the first scientific papers in the mid to late 1980s. Several systematic reviews and meta-analyses have evaluated the efficacy of structured exercise treatment in cancer.[2-6] For example, Speck et al. identified a total of 66 studies reported as ‘high-quality’ that examined the impact of exercise treatment in a broad array of oncology scenarios (e.g. differences in histological primary site, stage and treatment) on a total of 60 different primary end points in adults with cancer. Intriguingly, despite the degree of heterogeneity in how exercise was being utilized to manipulate physiological adaptation, the nature of the exercise prescription in the vast majority of studies was similar. More specifically, almost all prescriptions followed traditional guidelines consisting of either supervised or home-based endurance (aerobic) training or endurance training combined with resistance training, prescribed at a moderate-intensity (50–75% of a predetermined physiological parameter, typically age-predicted heart rate maximum or reserve), for two to three sessions per week, for 10 to 60 min per exercise session, for 12 to 15 weeks. Despite the adoption of a relatively homogeneous prescription approach, exercise training was, for the most part, associated with benefit across a diverse range of end points, largely irrespective of the oncology setting.
On this evidence, it could be argued that a standardized, largely homogeneous exercise prescription that adopts a conventional approach is safe, efficacious, and therefore sufficient. This has resulted in a limited perceived need to elucidate the optimal dose, sequencing, or combination of different training stresses to specifically alter a desired physiological end point in any clinical population, including oncology. However, the significant benefit of generically dosed exercise treatment on heterogeneous end points rather reflects the remarkable pleiotropic physiologic impact of exercise. Moreover, the use of generic exercise prescriptions (irrespective of clinical population or primary end point) is masking the full therapeutic promise of exercise treatment. Indeed, for more than half a century, exercise training has been continually refined, precisely dosed, and scheduled to minimize injury and optimize human/athletic performance; the basis of all training prescriptions in this arena adheres to fundamental tenets of human exercise physiology known as the principles of training. These tenets are rarely applied or even considered when designing exercise trials in clinical populations.[8, 9] Accordingly, the purpose of this Opinion paper is to provide an overview of the application of these principles in the design and conduct of clinical trials in exercise-oncology research. This paper will focus primarily on application of these principles to aerobic-based training, although the concepts also apply to resistance training or combination training programs.
The principles of training.
Oxygen consumption and ventilatory responses to incremental treadmill exercise in a 65 year-old woman with early-stage breast cancer. (A) Increasing workloads during the cardiopulmonary exercise test causes linear increases in oxygen consumption (VO2 in mL/kg/min) to the point of volitional fatigue at a VO2peak of 18.9 mL/kg/min. (B) A graphical representation of alveolar ventilation (VE in L/min) demonstrate two exponential ‘breakpoints’ in ventilation corresponding to Ventilatory Threshold 1 (VT1) and Ventilatory Threshold 2 (VT2). These thresholds demarcate the transition of low, medium, and high exercise intensity, and correspond to specific parameters that may be used for identification of relative intensity for exercise prescription and monitoring. These intensities and the corresponding ranges of physiological identification thereof (heart rate, blood pressure, and rating (Rtg) of perceived exertion on a 6–20 scale) provide an appropriate tool for indirect assessment of training stress and intensity.
Comparison of linear and nonlinear exercise prescriptions. Each bar represents a training session at prescribed workloads based on the absolute or relative intensity. (A) The conventional (linear) approach utilizes standard intensity, frequency, and duration parameters after an initial lead in period, with static increases in session duration (i.e. 20 to 45 min). (B) The alternative non-linear approach considers the principles of exercise training in order to optimize the adaptations to the exercise stimulus. Sessions are tailored to an individual's relative intensity, based on cardiopulmonary exercise testing or exercise tolerance testing, and specified to address a particular endpoint. Sessions and weeks progress over the course of the prescription and vary between low intensity (e.g. 55% VO2peak; white bars) and moderate (e.g. 75%; grey bars) and high intensity (e.g. 100% VO2peak; black bars) training in order to target various physiological systems involved in the cardiopulmonary response to exercise. Session intensity is inversely related to session duration, that is, sessions involving high relative intensity workloads are conducted in shorter bouts through short duration training sessions and are less frequent to ensure recovery between sessions. VO2peak, peak rate of oxygen consumption.
In the conventional approach (Figure 3A), exercise training intensity is prescribed using the heart rate reserve technique (a method based on chronological age and resting heart rate) without consideration of the patients' functional limitations or the primary study end point. This is the most common method of individualizing training in the oncology setting. Such an approach is problematic, however, given the 10 to 12–beat-per-minute variation in maximal heart rate in normal subjects.[35, 36] There may be even greater variation in cancer patients, given the documented impact of current or previous systemic therapy on autonomic function. This aerobic training intensity prescribed at 75% heart rate reserve (for example) may elicit very different physiologic adaptations between patients (because of the inaccuracy of age-predicted maximum heart rate and the decreased heart rate reserve due to elevated resting heart rate). Further, the majority of sessions within this prescription are performed at the same intensity and duration, as determined by their initial CPET or ETT; the workload prescribed to correspond with their percent heart rate reserve will no longer be appropriate after an initial adaptation period. In this instance, training volume remains constant and does not progress across the entire intervention. This is problematic considering that as cardiorespiratory fitness improves, the adaptation from an identical exercise stimulus diminishes; therefore, there is an insufficient stimulus to induce further physiologic adaptation. As such, this prescription fails to consider three important principles of training, namely individualization, specificity, and progressive overload.
Contrastingly, in the alternative exercise prescription approach, the use of appropriate baseline testing (i.e. CPET) permits aerobic training to be tailored to a patients’ baseline VO2peak (Figure 2), and thereby adhering to the principle of individualization. Second, the intensity, duration, and occasionally, the frequency of training sessions are sequenced in such a fashion that training volume is continually increased across the entire program (i.e. the principles of specificity and progressive overload). This approach also adds important variety to the prescription that not only continually alters the exercise ‘stress’ (to optimize adaptation) but can also stimulate patient interest and motivation. Third, training intensity is sequenced, such that higher intensity or higher volume training is followed by lower intensity (recovery) training and rest days to optimize adaptation (i.e. the principle of rest and recovery). Finally, although not specifically outlined in Figure 3B, the principle of reversibility may be a particularly important consideration in aerobic training trials conducted in oncology populations because patients may be forced to temporarily discontinue training because of therapy-induced toxicity and/or disease progression. Detraining effects can occur rapidly (within days to weeks), thus, subsequent training sessions may need to be resumed at reduced duration and intensity than initially planned. Such dose reductions will also impact training efficacy.[40-42]
Despite the proven efficacy in the arena of sports/athletic performance, consideration of the principles of training has not been translated into the design of exercise prescriptions in clinical populations. Indeed, to our knowledge, only one trial to date has compared the efficacy of an exercise prescription following a non-linear approach vs. a traditional linear approach in any clinical population. Specifically, Klijn et al. compared the efficacy of non-linear periodized training with that of traditionally-prescribed linear combined aerobic and resistance training in 110 patients with severe chronic obstructive pulmonary disease. Exercise training in both arms was performed three times a week for 10 weeks. Results indicated that non-linear exercise training was associated with superior improvements in cycling endurance and health-related quality of life compared with linearly prescribed training. It is important to state that a common perception is that studies examining the efficacy of high-intensity interval training (HITT) also adhere to the principles of training / non-linear approach. However, if studies exclusively test HITT (i.e. all exercise sessions are HITT) and proceed without appropriate progression, then these programs are also linear in design and do not adhere to the principles of training. In the oncology setting, approximately six studies to date have examined the safety, tolerability, and preliminary efficacy of non-linear aerobic training, compared with a usual care (no exercise training) control group. As presented in Table 1, exercise prescriptions adhering to a non-linear approach appear to be safe (low adverse event rate), tolerable (mean adherence ≥75% of prescribed sessions both during and after primary adjuvant therapy), and efficacious, conferring favourable improvements in VO2peak, quality of life, and other physiological outcomes. On the basis of this data, our group is comparing the efficacy of either non-linear periodized training or traditionally prescribed linear aerobic training with an attention control group (i.e. supervised progressive stretching) in 174 women completing primary therapy for early-stage breast cancer. Aerobic training in both arms is being performed four times a week for 16 weeks. The primary end point is VO2peak.Exercise training studies adopting a non-linear approach in exercise-oncology research (chronological order)
|Authors||Population/setting/design/N||Non-linear aerobic exercise training intervention||Major findings|
|Jones et al. 2007||Operable lung cancer/pre-operative/prospective single-group/25||Duration: 4–6 weeks||Adverse events: Abnormal decline in systolic blood pressure >20 mmHg, which normalized after exercise determination (n = 2)|
|Frequency: five times a week|
|Modality: cycle ergometry||Adherence: 72% (number of sessions attended divided by the total number of sessions prescribed)|
|Week 1: five sessions: 20 min at 60%; VO2peak up to 30 min at 65% VO2peak|
|Weeks 2–3: four sessions: 25–30 min at 60–65% VO2peak; one session: 20–25 min at VTa||Outcomes: ITT: VO2peak increased 2.4 mL/kg/min (P = 0.002) and 6 MWD increased 40 m from baseline to pre-surgery; No significant change in any pulmonary function outcome was observed from baseline to pre-surgery (P > 0.05). PPA: Adherence > 80% (n = 12): VO2peak increased 3.3 mL/kg/min (P = 0.006) and 6MWD increased 49 m (P = 0.013)|
|Week 4+: three sessions: 25–30 min at 60–65% VO2peak; one session: 20–25 min at VT; one session: 10–15 times (30–60 s at VO2peak, followed by 60 s of active recovery)|
|Jones et al. 2008||Non-small cell lung cancer (Stage I–IIIb)/post-surgical /prospective single-group/20||Duration: 14 weeks||Adverse events: none|
|Frequency: three times a week|
|Modality: cycle ergometry|
|Week 1: three sessions: 15–20 min at 60% Wmax||Adherence: 85% (number of sessions attended divided by the total number of sessions prescribed)|
|Weeks 2–4: three sessions: increased progressively to 30 min at 65% Wmax|
|Week 5–6: two sessions: 30–45 min at 60–65% Wmax; one session: 20–25 min at VT||Outcomes: ITT: VO2peak increased 1.1 mL/kg/min (P = 0.11) and Wmax increased 9 W (P = 0.003). Significant favourable changes were also observed for functional well being (P = 0.007) and fatigue (P < 0.03). PPA: Patients not receiving adjuvant chemotherapy (n = 11): VO2peak increased 1.7 mL/kg/min (P = 0.008). Peak heart rate (P = 0.05), Wmax (P < 0.001), and workload @ VT (P = 0.05) also increased. Patients receiving adjuvant chemotherapy (n = 8): VO2peak at VT decreased (P = 0.03)|
|Week 7–10: two sessions: 30–45 min at 60–70% Wmax; one session: 20–30 min at VT|
|Week 10–14: two sessions: 30–45 min at 60–70% Wmax; one session: 10–15 times (30 s at VO2peak, followed by 60 s of active recovery)|
|Courneya et al. 2008||Mild-to-moderately anaemic patients with solid tumours/during or post-cancer therapy/single-centre, two-armed randomized controlled trial comparing darbepoetin alfa (an erythropoiesis-stimulating agent) alone vs. darbepoetin alfa plus aerobic training/55||Duration: 12 weeks||Adverse events: none|
|Frequency: three times a week||Adherence: 85% (number of sessions attended divided by the total number of sessions prescribed)|
|Modality: cycle ergometry||Outcomes: VO2peak was significantly greater in the exercise group (+3.0 mL/kg/min; P < 0.001), as were Wmax (P = 0.028) and VT (P = 0.001). The exercise group showed trends towards a more rapid hemoglobin response with less drug administration compared with the non-exercise group (P = 0.07–0.12)|
|Intensity: 60–100% of baseline Wmax|
|Courneya et al. 2009||Lymphoma/during chemotherapy or following treatment / single-centre, two-armed randomized control trial comparing usual care vs. usual care plus aerobic exercise training/122||Duration: 12 weeks||Adverse events: none|
|Frequency: three times a week|
|Modality: cycle ergometry|
|Week 1–4: three sessions: 15–20 min at 60% Wmax, increasing 5% per week to 75% by Week 4||Adherence: 78% (duration and intensity criteria were met during 99.0% and 90.7% of sessions)|
|Week 5–7: three sessions: 15–20 min at 75% Wmax, increasing 5 min per week to 25–30 min by Week 9|
|Week 7–8: two sessions: 30–35 min at 75% Wmax, increasing 5 min to 35–40 min in Week 8; one session: exercise at VT (time N/R)||Outcomes: Aerobic training was superior to usual care on all indicators of cardiovascular fitness, including VO2peak (+5.2 mL/kg/min), Wmax, (+28 W) and VT (+0.33 L/min) (P < 0.001). Aerobic training was superior to usual care for patient related physical functioning, quality of life, fatigue, happiness and depression (P < 0.05). Aerobic training did not interfere with treatment completion or response.|
|Week 9–12: two sessions: 30–35 min at 75% Wmax, increasing 5 min per week to 40–45 min by Week 9 to Week 12; one session: interval training at VO2peak (time N/R)|
|Hornsby et al. 2013||Operable breast cancer (stage IIb–IIIc)/receiving neo-adjuvant chemotherapy/single-centre, two-armed randomized control trial comparing neoadjuvant AC alone vs. AC plus aerobic exercise training/20||Duration: 12 weeks||Adverse events: During baseline exercise testing: exercise-induced oxygen desaturation (SpO2 < 84%) (n = 1), anxiety attack (n = 1), and dizziness (n = 1). All symptoms/signs resolved promptly upon cessation of exercise and did not preclude study participation; During training: Unexplained leg pain that resolved following exercise cessation (n = 1).|
|Frequency: three times a week|
|Modality: cycle ergometry|
|Week 1: three sessions: 15–20 min at 60% Wmax||Attendance: 82% (number of sessions attended divided by the total number of sessions prescribed)|
|Weeks 2–4: three sessions: increased progressively to 30 min at 65% Wmax|
|Week 5–6: two sessions: 30–45 min at 60–65% Wmax; one session: 20–25 min at VT||Adherence: 66% (number of sessions successfully completed divided by the number of planned sessions attended. Non-adherence was defined as any exercise session requiring exercise dose modification of either the planned exercise duration or intensity.|
|Week 7–10: two sessions: 30–45 min at 60–70% Wmax; one session: 20–30 min at VT||Outcomes: ITT: VO2peak increased by 2.6 mL/kg/min (+13.3%) in the aerobic training group and decreased by 1.5 mL/kg/min (−8.6%) in the AC alone group (mean difference +4.1 mL/kg/min, P = 0.001). Differences between groups were also observed for Wmax and oxygen pulse (P < 0.05).|
|Week 10–12: two sessions: 30–45 min at 60–70% Wmax; one session: 10–15 times (30 s at 100% Wmax, followed by 60 s of active recovery)|
|Jones et al. 2014||Localized (stage I–II) prostate adenocarcinoma/post bilateral nerve sparing radical prostatectomy / single-centre, two-armed randomized control trial comparing usual care alone vs. usual care plus aerobic exercise training / 50||Duration: 6 months||Adverse Events: Ischemic ECG changes reflected by significant ST segment depression were observed in three patients during baseline CPET. 129 independent non-serious adverse events occurred that required modification or early cessation of the exercise training prescription. The majority of events were training-induced leg cramps (55%) or back pain (26%).|
|Frequency: five times a week (minimum three supervised, then two supervised or home setting)||Attendance (supervised): 83% (number of sessions attended divided by the total number of sessions prescribed)|
|Modality: treadmill walking||Compliance (supervised): 79% (number of sessions successfully completed divided by the number of planned sessions attended. Non- adherence was defined as any exercise session requiring exercise dose modification of either the planned exercise duration or intensity.|
|Duration and intensity: non-linear prescription aimed to meet 30–45 min/session at 55–100% of VO2peak. Intensity based on treadmill speed/grade corresponding %VO2peak elicited during the pre-randomization or mid-point CPET.||Outcomes: VO2peak increased 1.9 mL/kg/min (P = 0.016) and brachial artery flow mediated dilation increased 1.4% (P = 0.03) in the aerobic training group compared with usual care. There were no significant between-group differences in any erectile function subscale. There were significant correlations between exercise training adherence and change in FMD (r = 0.38; P = 0.081) and VO2peak (r = 0.57; P = 0.003) but not between exercise training adherence and any erectile function end points.|
The purpose of this commentary was to provide an overview of the application of the fundamental principles of training in the design and conduct of clinical trials in exercise-oncology research. It is hoped that attention to these issues will provide the platform for constructive dialogue with the view towards the development of best practice guidelines to optimize exercise training in the oncology setting. Application of these guidelines will ensure continued progress in the field by producing the high-quality evidence base necessary to convince oncology professionals that exercise training is an integral aspect of the therapeutic armamentarium in the treatment and control of cancer.
The authors certify that they comply with the ethical guidelines for authorship and publishing of the Journal of Cachexia, Sarcopenia and Muscle (von Haehling S, Morley JE, Coats AJS, Anker SD. Ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle. J Cachexia Sarcopenia Muscle. 2010;1:7–8.)
J.F.C. is supported by Research Grants from TRYGFONDEN, the Novo Nordic Foundation, the Danish Cancer Society, and the Beckett Foundation. L.W.J. is supported in part by research grants from the NCI and AKTIV Against Cancer.