Randomization and blinding
After completing all baseline assessments, patients will be randomly assigned to either the exercise training group or usual care group in a 1:1 ratio using block randomization. A research assistant, not otherwise involved in the trial, will generate the block sizes and randomization sequence using a computer-generated random allocation sequence which will be concealed from the recruiting study coordinator. Given the nature of the intervention, it is not possible to blind the investigators or participants to group allocation. Additionally, due to logistical challenges at our facility, it is difficult to blind outcome assessors to group allocation for the primary outcome of cardiorespiratory fitness and the secondary outcomes of functional fitness. Nevertheless, fitness outcome assessors will follow a detailed protocol and be trained in the importance of standardizing outcome assessments and avoiding bias. Moreover, outcome assessors will not review the metabolic data during the cardiorespiratory fitness test, and the criteria for achieving peak volume of oxygen consumption (VO2 peak) will undergo an independent review. Finally, outcome assessors will be blinded to group assignment for the exploratory outcomes of treatment toxicities, treatment completion, treatment response, and surgical complications which will be assessed by medical staff not otherwise involved in the study.
Intervention
For patients randomized to the exercise training group, the intervention will be divided into two phases: (1) during NACRT and (2) post NACRT. During NACRT, all of the exercise sessions will be supervised by a certified exercise physiologist. We previously determined that it was feasible for patients to attend supervised exercise sessions at our fitness center (within a 5-min walk from the cancer center) since they were already coming to the cancer center 5 days/week for radiation treatment [
16]. During NACRT, patients will be asked to complete 18 supervised HIIT sessions (i.e., three sessions/week for 6 weeks) and to continue with any light-to-moderate-intensity exercise that they were performing at baseline. We selected a HIIT program for evaluation because of its ability to maximize cardiorespiratory fitness improvements over a short period of time [
18]. Moreover, HIIT has previously demonstrated safety and feasibility in clinical populations including patients with cardiometabolic disease [
19], diabetes [
20], and during adjuvant chemotherapy in patients with mixed cancers [
21]. HIIT is characterized by relatively short bursts of vigorous-intensity exercise, interspersed by periods of rest or light-intensity exercise for recovery. There are an endless number of possible combinations that can make up a HIIT program; however, HIIT typically refers to exercise intensities corresponding to ≥ 85% of peak heart rate or ≥ 80% of VO
2 peak [
19]. We have designed the HIIT program in the EXERT trial to closely match a previously published HIIT program which has demonstrated feasibility, safety, and greater improvements in cardiorespiratory fitness in patients with coronary artery disease [
22].
In our phase I study, we demonstrated an excellent median attendance rate of 83% to three sessions/week of moderate-intensity, continuous exercise training during NACRT [
16]. Moreover, no adverse events were observed and our evaluation was that even higher-intensity exercise training would be feasible in this clinical setting. Nevertheless, the safety and feasibly of HIIT during NACRT in rectal cancer patients has yet to be established and is a key objective of our study.
In our feasibility study, the most frequently used modality was the treadmill (67.4% of sessions) [
16]. Thus, the HIIT program will consist of uphill treadmill walking. Each HIIT session will start with a 5-min warm-up at a workload that elicits 30-40% of VO
2 peak during the baseline graded exercise test. Patients will complete 2-min, high-intensity intervals at a workload that elicits 85% of VO
2 peak during the baseline graded exercise test. Between the high-intensity intervals, the active-recovery intervals will consist of 2 min at a workload that elicits 40% of VO
2 peak during the baseline graded exercise test. Each HIIT exercise session will end with a 5-min cool-down totaling 40 min/session. The number of HIIT intervals will begin at five and progress by one every second session up to eight intervals (Table
1).
Table 1
High-intensity interval training program during neoadjuvant chemoradiotherapy in the Exercise During and After Neoadjuvant Rectal Cancer Treatment (EXERT) trial
1–2 | 5 | 2 | 85 | 4 | 2 | 40 | 28 |
3–4 | 6 | 2 | 85 | 5 | 2 | 40 | 32 |
5–6 | 7 | 2 | 85 | 6 | 2 | 40 | 36 |
7–18 | 8 | 2 | 85 | 7 | 2 | 40 | 40 |
Prior to each exercise session, an exercise specialist will assess blood pressure and heart rate and ask patients to report any immediate symptoms. Additionally, body temperature will be assessed in patients reporting any signs or symptoms of a fever. If body temperature is ≥ 38 °C, patients will be instructed not to exercise that day. For each supervised session, the exercise specialist will record attendance and the workload (i.e., treadmill speed and incline), Rating of Perceived Exertion (RPE) (Borg 0–10), and heart rate for each high-intensity interval. Optimal adherence to the supervised exercise sessions will be facilitated by scheduled appointments, flexibility in scheduling the exercise sessions (i.e., according to patients’ radiation sessions), immediate follow-up and re-booking of missed sessions, personable exercise trainers, and free parking. In our feasibility study, we identified the most common barriers to exercising during NACRT as side effects from chemoradiotherapy (88%), fatigue (76%), and diarrhea (71%) [
23]. In the EXERT trial, we will optimize adherence to the supervised exercise sessions by modifying each session according to any immediate symptoms or side effects that patients are experiencing.
If a patient is experiencing immediate side effects that hinder their ability to complete the high-intensity intervals at the prescribed workload, the fitness attendant will modify the exercise session according to what the patient is able and willing to do. Options for modifying the exercise dose will include either reducing the workload of the high-intensity intervals, reducing the number of high-intensity intervals, or both. All reasons for dose modification will be noted.
After NACRT, patients will be asked to complete at least 150 min of unsupervised, moderate-to-vigorous-intensity, continuous exercise training training/week (current Canadian Physical Activity Guidelines). In our phase I study, it was feasible for patients to achieve 150 min of mostly unsupervised, moderate-intensity exercise/week after NACRT. Although local patients in our pilot study were offered a supervised exercise program after NACRT, only two out of 16 patients expressed interest in continuing with supervised exercise in this phase and patients mainly achieved their weekly exercise minutes by walking outdoors or by using pre-existing home exercise equipment (e.g., treadmill, elliptical, and upright bike). For this reason, we felt that it would be difficult to deliver a standardized and replicable HIIT program after NACRT. Moreover, in our phase I study, cardiorespiratory fitness improved by 2.4 ml/kg/min from post NACRT to pre surgery suggesting that an unsupervised, moderate-intensity, continuous exercise training program may be effective at improving cardiorespiratory fitness after NACRT and prior to surgery in rectal cancer patients. Finally, after our experience in the phase I study, we felt that it would be feasible and safe for rectal cancer patients to complete moderate-to-vigorous-intensity continuous exercise in this phase and may result in greater improvements in cardiorespiratory fitness. Nevertheless, one of the goals of the EXERT trial is to further establish the feasibility and safety of continuous exercise training after NACRT and to determine its preliminary efficacy at improving outcomes for rectal cancer patients.
After NACRT, the exercise will be individualized according to patients’ post-NACRT graded exercise test (i.e., heart rate that corresponded with approximately 46–91% of VO
2 peak) [
24]. Patients will be provided with a heart rate monitor and will also be instructed on how to use RPE and the talk-test to determine the intensity of their exercise sessions. Patients will be provided with examples of how to complete the exercise (e.g., 30 min, 5 days/week; 50 min, 3 days/week). Moreover, patients will be instructed that the exercise completed in this phase should be in addition to what they were already doing at baseline. Finally, patients will receive printout materials with instructions on how to complete the exercise in the post-NACRT phase as well an exercise log to help them keep track of their exercise. After NACRT, optimal adherence will be achieved using a more formal behavioral support program based on the Theory of Planned Behavior (TPB) [
25]. The study coordinator will maintain weekly contact with each patient via telephone and offer behavioral support sessions consisting of standard behavioral change techniques including goal setting, planning, self-monitoring, and overcoming barriers.
Usual care group
Patients randomized to the usual care group will receive standard medical care which includes meeting with a dietician weekly to ensure adequate caloric and nutrient intake. Patients in the usual care group will be asked not to increase their physical activity/exercise levels during or after NACRT. Exercise is not currently part of standard care for these patients at our center and patients do not receive any exercise recommendations. After the pre-surgery assessment, patients in the usual care group will be offered a copy of the Canadian Physical Activity Guidelines and encouraged to initiate an exercise program after they recover from surgery and receive medical clearance from their physician.