Structured exercise training (i.e., aerobic, resistance, or combination thereof) has gained increased attention after a cancer diagnosis to either off-set anticancer treatment-related acute and chronic toxicities (1–5) or as a potential anticancer therapy (6–9). A field known as exercise-oncology. Parallel efforts by the American College of Sports Medicine and other organizations are encouraging health professionals to include exercise when designing treatment plans for patients with or at risk for chronic disease (10). The foundation of these efforts is built on the rigor and quality of the conduct (methods) and reporting of randomized controlled trials (RCT) of exercise treatment in a given population. The Consolidated Standards of Reporting Trials (CONSORT) guidelines (11) and the elaboration for nonpharmacological trials (12) provide excellent frameworks for the general conduct and reporting of RCT but do not provide standards and processes for aspects unique to exercise RCT.
Arguably, the most important methodological consideration when designing an exercise RCT is consideration of the fundamental components of an exercise prescription (e.g., frequency, intensity, and modality) and principles of training (13). Unfortunately, description of these components in exercise-oncology trials is often missing or incomplete (14,15), seriously hindering study reproducibility, interpretation, and cross-study integration. This lack of information also precludes quantification of the “planned” exercise treatment dose. Several quantitative methods are available to determine exercise treatment dose in humans (e.g., average heart rate, rate of perceived exhaustion (16), duration in heart rate zone (17), and training impulse), and although widely used in athletic populations, such metrics are rarely used in exercise-oncology RCT.
Reporting of adherence (tolerability) to a planned prescription of exercise treatment is typically limited to rates of lost-to-follow-up (LTF; e.g., number completing follow-up assessments) and attendance (e.g., the ratio of attended to planned treatments) (18–20). However, these variables may provide limited insight into the actual tolerability of exercise and do not permit accurate quantification of “completed” exercise dose. In oncology trials, drug dose quantification (e.g., total cumulative dose) and tolerability (e.g., rates of permanent treatment discontinuation, dose modification, and dose interruption) are systematically monitored and reported according to standardized and widely accepted methods and definitions (21–23). Whether these metrics have utility in exercise-oncology trials has not been investigated.
Against this background, we explored whether standard methods adapted from athletic performance and oncology drug trials have utility for reporting of the exercise treatment prescription and adherence (tolerability) in a previously reported RCT of aerobic training in patients with prostate cancer (24).
Patients and eligibility
Full details regarding the study sample, recruitment, and procedures have been reported previously (24). Men with histologically confirmed localized prostate cancer after prostatectomy at Duke University Medical Center (DUMC) were eligible. Other major eligibility criteria were as follows: 1) no absolute contraindications to a maximal cardiopulmonary exercise test (CPET), 2) willingness to travel to DUMC to attend supervised training sessions, and 3) a peak oxygen consumption (V˙O2peak) below sex-/age-matched sedentary values. All study procedures were reviewed and approved by the DUMC institutional review board. All subjects signed a written consent form before the initiation of any study-related procedures.
Study design and treatment
In this two-arm RCT, eligible patients were randomized with an allocation ratio of 1:1 to 1) aerobic training or 2) usual care for a total of 24 wk. Patients were followed up for 24 wk or until disease progression or withdrawal of consent. Full details regarding the aerobic training therapy prescription have been reported previously (24). In brief, patients received an aerobic training regimen of 72 supervised treadmill walking sessions delivered thrice weekly for 24 consecutive weeks. The intensity of each session alternated between five different doses (i.e., 55% (zone 1), 65% (zone 2), 75% (zone 3), 85% (zone 4), 100% (zone 5)) of maximal MET expenditure (i.e., V˙O2peak). Zone 5 sessions consisted of acute bouts ranging from 30 s to 2 min in duration at peak workload followed by at least 1 to 3 min of active recovery for 4 to 20 intervals.
The actual intensity was individualized to each patient on the basis of workload (i.e., treadmill speed/grade) corresponding to a specific percent of V˙O2peak directly measured during the prerandomization or midpoint (week 12) CPET. The CPET was performed on a treadmill with expired gas analysis (ParvoMedics TrueOne 2400, Sandy, UT) (25). Treatment dose was sequenced in such a fashion that exercise-induced physiological stress was continually altered in terms of intensity and duration in conjunction with appropriate rest and recovery sessions to optimize physiological adaptation across the entire intervention period (i.e., nonlinear, periodized training) (13).
The planned intensity, duration, and sequencing of all treatment sessions are shown in Figure 1. Safety and verification of dose intensity of each session was evaluated using a combination of heart rate (continuous assessment throughout entire session), blood pressure (every 10 min), and rate of perceived exertion (every 10 min). Reduction in treatment dose (via intensity (treadmill speed or grade) or duration)) of any session was permitted because of health-related (e.g., elevated heart rate beyond target zone and excessive fatigue) or non–health-related events (e.g., time constraints). The nature and magnitude of dose reduction was at the discretion of the exercise physiologist monitoring each session.
Planned dose of all sessions was quantified as METs per session. The planned intensity of each session was multiplied by the corresponding session target intensity duration (8–45 min) to calculate METs per session; all sessions were summed to derive total planned cumulative MET-hours per patient (26). Treatments in weeks 1 to 12 and 13 to 24 were quantified using baseline and midpoint CPET data, respectively. Calculation of completed MET was quantified as the actual intensity and duration of each attended session. All sessions were summed to derive total completed cumulative MET-hours per patient. Relative dose intensity (RDI) was defined as the ratio of total completed to total planned cumulative dose, expressed as a percentage. An RDI of 100% indicates that the aerobic training regimen was administered at the planned dose per protocol without any early session termination or dose modification.
Adherence (tolerability) outcomes
Conventional exercise trial–related tolerability variables were rates of LTF (number completing follow-up assessments) and attendance (ratio of total attended to planned treatments). Exploratory oncology drug trial–adapted adherence (tolerability) outcomes were as follows: permanent treatment discontinuation, permanent discontinuation of aerobic training before week 24; treatment interruption, missing at least three consecutive sessions; dose modification, at least one session requiring dose reduction during training and the total number of sessions requiring dose modification; early session termination, at least one session requiring early termination; and pretreatment intensity modification, the intensity of at least one session required modification (e.g., planned 65% V˙O2peak modified to 55% V˙O2peak because of a preexercise screening indication (e.g., fatigue and time constraints)). Rescheduling of missed sessions was permitted within the study intervention period. Safety was evaluated by the frequency of serious and nonserious events occurring during any supervised aerobic training treatment session. All events were recorded in the patients’ case report form by the exercise physiologist monitoring each treatment. All compliance variables are collectively counted as one entity in the same patient unless otherwise indicated (27).
Baseline medical and demographic characteristics of each group are summarized using descriptive statistics (mean/SD and frequencies). Aerobic training dose and tolerability variables are summarized by mean (SD and range, where appropriate), including all patients initially randomized to the aerobic training group (i.e., n = 25). All variables are presented under the intention-to-treat principle (ITT; i.e., regardless of adherence to the aerobic training prescription).
Details regarding response rates, patient profile, and primary efficacy and safety data have been reported previously (24). Characteristics of the patients assigned to aerobic training are presented in Table 1. Mean V˙O2peak increased +2.6 mL O2·kg−1·min−1 in the aerobic training group (P < 0.001) compared with +0.4 mL O2·kg−1·min−1 in the usual care group (P = 0.461) (24). For the ITT cohort, the delta percent change in V˙O2peak ranged from −15% to +32%. No serious (life-threatening) adverse events were observed during CPET procedures or aerobic training treatment sessions.
Treatment Dose Quantification and Tolerability
Planned and completed treatment dose
Planned dose of aerobic training per week was 8.4 ± 2.5 MET·h·wk−1 (range, 4.1–12.1 MET·h·wk−1; Fig. 2A), equating to a total cumulative planned dose of 200.7 ± 47.6 MET·h (range, 123.9–304.6 MET·h; Fig. 2B). Completed dose per week was 6.4 ± 4.1 MET·h·wk−1 (range, 3.8–8.6 MET·h·wk−1; Fig. 2A), equating to a total cumulative completed dose of 153.8 ± 68.8 MET·h (range, 19.7–291.4 MET·h; Fig. 2B). The mean RDI was 77% ± 25% (range, 18.4%–100.0%; see Figure, Supplemental Digital Content 1, Relative dose intensity calculated as total “delivered” cumulative dose divided by the total planned cumulative dose to derive relative dose intensity, http://links.lww.com/MSS/B188).
Conventional and exploratory adherence variables are summarized in Table 2. For conventional metrics, 2 of the 25 patients did not complete follow-up assessments at week 24, an LTF rate of 8%. The overall mean attendance was 79% ± 26% (range, 19%–100%). For exploratory variables, a total of 6 (24%) patients permanently discontinued aerobic training before week 24, with treatment being discontinued in weeks 7, 10, 12, 14, 15, and 18 owing to health-related and non–health-related reasons (Table 2). Aerobic training was interrupted in 11 (44%) of 25 patients. The main reasons for treatment interruption were non–health-related reasons (e.g., vacation). A total of 24 (96%) of 25 patients required at least one treatment to be dose reduced, with a total 185 (10%) of 1800 sessions requiring dose reduction because of both health-related and non–health-related reasons (Table 2; Fig. 3A). On the basis of zone, the degree of dose modification was higher for zone 3, 4, and 5 training sessions (mean, 14%) compared with zone 1 and 2 training sessions (mean, 8%), but comparable across zones (zone 3 (13%), zone 4 (13%), and zone 5 (17%); Fig. 3B). More than 50% of all higher-intensity training sessions that required dose modification were done so in only 6 (24%) patients. A total of 14 (56%) of 25 patients required the intensity of at least one session to be dose reduced before session initiation, with a total of 33 sessions (2%) required before session modification. A total of 18 (72%) patients required at least one session to be terminated early because of health-related nonserious adverse events (e.g., elevated exercise heart rate (out of zone) and excessive fatigue) or non–health-related reasons; a total of 59 (3%) sessions required early termination.
The CONSORT guidelines (12) and the elaboration for nonpharmacological trials (11) provide a general framework for reporting the methods of randomized trials but lack specificity. For instance, in terms of intervention methods, the nonpharmacological CONSORT standards recommend reporting: “Precise details of both the experimental and comparator. Description of the different components of the interventions” (sections 4 and 4A) (12). However, such a statement is open to considerable interpretation, with precise description of intervention components largely at the discretion of the investigators. Arguably, a minimum requirement when reporting the methods of an exercise intervention trial is inclusion and precise description of all fundamental exercise prescription components. However, recent systematic reviews of exercise-oncology trials found that only 2 (3%) of 62 studies described all exercise prescription components and adhered to each component (14,15). Furthermore, when reported, description of the prescription component(s) is often vague or imprecise. For example, the reporting of the planned intensity of treatment sessions is often described using wide dosing ranges (e.g., 60%–80% of maximal heart rate (HRmax)). Although investigating prescriptions that encompass exercise training sessions between 60% and 80% of HRmax are reasonable, the optimal duration and physiological adaptations associated with sessions conducted within this broad range are distinct (13). Unfortunately, details regarding the number of sessions conducted at a specific intensity or duration are often not reported; thus, it is not possible to discern the level of interpatient heterogeneity in the exercise prescription dose investigated.
Another example is inadequate description of individualization of training dose intensity. The nonpharmacological CONSORT standards recommend reporting: “descriptions of the procedure for tailoring the intervention to the individual participants” (section 4A) (12). Again, the definition of “tailoring” may have several interpretations. In exercise physiology, individualization is defined as the customized application of training toward the physiological status of the patient (13). Clearly, even within carefully selected homogenous cohorts, considerable heterogeneity likely still exists in baseline exercise capacity, exercise history, and interpatient medical profile. Unfortunately, individualization or tailoring of exercise treatment in oncology trials is either not reported at all (14,15) or, if reported, tailored on the basis of age-predicted HRmax. Such an approach may be limited, however, because of the 10- to 12-bpm variation in HRmax in healthy subjects (28,29), with potentially even greater variation in cancer patients, given the documented effect of certain anticancer therapies on cardiac function (30). Application of intensity dosing based on estimated HRmax could therefore result in either an underdosing or overdosing of exercise treatment in a given patient. Full consideration of all exercise prescription components will also permit quantification of total cumulative exercise dose. Of the many methods available (31,32), here we quantified treatment dose using MET because it is the universally accepted metric for exercise dose quantification in epidemiological research (33–35). The use of MET in this trial was appropriate because CPET procedures provide direct assessment (via metabolic analysis) of MET at rest and during exercise. This, in turn, permitted estimation of MET expenditure of each exercise treatment session and, therefore, the total cumulative dose of the planned prescription. Use of CPET procedures is considered standard practice in exercise trials among patients with chronic respiratory disease and cardiovascular disease (36), with an increasing number of trials using this tool in exercise-oncology research (37); as such, the approach used to quantify planned treatment dose in the present trial is generalizable to other trials in exercise-oncology research.
Full reporting of exercise prescription methods is arguably futile without parallel precise reporting of exercise treatment adherence (tolerability). The CONSORT standards for nonpharmacological trials (12), as well as the recent Consensus on Exercise Reporting Template (20), provide limited guidance. The widely reported that metrics exercise trials are the rates of LTF and attendance. In the present trial, rates of LTF and attendance were 8% and 79%, respectively, consistent with that reported in prior trials (19). Novel methods explored here, however, indicate that LTF and attendance may provide limited insight into the true tolerability of exercise treatment. For instance, although two patients were LTF, six (24%) permanently discontinued exercise treatment before week 24. Furthermore, attendance simply provides data on the number of planned treatment sessions missed but no information on the timing of missed sessions or adherence to prescribed dose. The dose interruption rate (missing ≥3 consecutive treatments) in the present trial was 44%. Presentation of such data not only provides important data regarding the tolerability of treatment but also may reveal patterns when patients are more likely to miss consecutive treatments or explain null findings. It is noteworthy that virtually all patients required the dose of at least one session to be reduced, with almost 10% of all planned treatment requiring a dose reduction. The attendance rate for these sessions, however, would be reported as 100%, indicating the limited insight provided by this metric. The present findings also indicate that the extent of dose modification was higher for higher-intensity exercise sessions (i.e., zones 3, 4, and 5) compared with lower-intensity sessions (i.e., zones 1 and 2), potentially leading to the conclusion that higher-intensity exercise training may have limited feasibility or tolerability in men with localized prostate cancer. However, the overall dose modification rate for these sessions was low overall (14%) and comparable across zones (range, 13%–17%); furthermore, >50% of these sessions were modified in only six patients. On the basis of these data, we contend that higher-intensity training is feasible/tolerable (and safe) for most patients in this setting, but not all patients—there is variability in exercise feasibility/tolerability. An important objective for future work is the conduct of phase 1/2-esque studies specifically designed to evaluate the safety and tolerability of exercise training in specific settings and identify the characteristics of patients for which exercise is feasible/tolerable as well as those for which exercise is not (9). These critical vanguard studies will not only evaluate the true tolerability of exercise in cancer populations but also inform the eligibility criteria for future definitive trials testing the efficacy of exercise in a particular clinical setting.
An added advantage of quantification of total planned dose together with use of novel treatment adherence metrics is that it permits accurate quantification of the completed treatment dose. Several trials have reported duration in target heart rate zone as a measure of completed dose, but although this metric provides superior information than attendance, reliance on heart rate is limited in certain clinical populations because heart rate response to exercise is often abnormal due to concomitant medications (e.g., beta-blockers and polychemotherapy). As a potential complementary approach, we calculated the ratio of completed to planned total cumulative dose to calculate RDI—a widely used metric in oncology drug trials. Although cross-trial comparisons are not yet possible, the mean RDI of 77% demonstrates that the planned exercise dose was, for the most part, adequately completed and therefore tested in the present trial.
This study has several important limitations. First, the generalizability of these exploratory retrospective findings is limited to a small cohort of relatively healthy men with localized disease not receiving any form of anticancer therapy. Larger, prospective studies across diverse oncology scenarios are required. Second, we only evaluated the utility of the selected adherence (tolerability) metrics to a supervised RCT of aerobic training; the applicability to nonsupervised or resistance training requires investigation, as does accurate monitoring of nonprotocol exercise and general physical activity (38). Third, we did not directly assess MET expenditure during aerobic training sessions but rather estimated MET expenditure on the basis of CPET data (at baseline or midpoint), potentially leading to miscalculation of the completed dose. Finally, in this report we focused out attention on the aerobic training (intervention) group, but equally important is monitoring of patients allocated to comparator groups, especially the degree of physical activity/exercise performed by patients assigned to nonexercise control groups (i.e., contamination) (38).
In summary, conduct and reporting methods adapted from athletic performance and oncology pharmacological trials may provide a novel and important approach for the conduction and reporting of exercise treatment trials in cancer.
The authors would like to thank Whitney Underwood for administrative support.
This study was supported by a research grant from the National Cancer Institute (R21-CA133895) awarded to L. W. J., T. S. N., L. W. J., J. S., C. C., and M. M. are supported by the Kalvi Trust, AKTIV Against Cancer, and the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). The authors declare no conflict of interests.
The results of the present study do not constitute endorsement by the American College of Sports Medicine and are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.
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CANCER; PROSTATE CANCER; EXERCISE ONCOLOGY; SAFETY; TOLERABILITY; TRAINING DOSE
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