The study was approved by the Institutional Review Board at the University of Utah and was in accordance with the Declaration of Helsinki. All participants provided written informed consent prior to participation. We used a restricted randomization design to ensure a balanced allocation into the arms of the study. This exploratory pilot study took place in an academic health science center setting. Participants were allocated to a RENEW intervention or a usual-care control group (Usual-Care) after using randomized blocks of varying length (2 and 4), to approximate balance between treatment arms. Sealed group assignment envelopes were opened after screening and consent were completed. Because this was an exploratory pilot study and it was important to have adequate numbers in each group, after a dropout the next group assignment was to that respective group as a replacement. Outcome measures were assessed by study personnel blinded to group assignment at baseline and at the end of the intervention period (12 weeks).
Recruitment and Eligibility
We employed a two-part approach to recruitment from 2006-2008 which included receiving names and identifying information from: 1) clinical databases at the University of Utah and Huntsman Cancer Institute, and 2) individuals responding to announcements in a Salt Lake City daily newspaper, or via word of mouth referral. This exploratory pilot study was designed to recruit a sample of 40 cancer survivors, 20 participants randomized to each group (RENEW and Usual-Care). The a priori sample size calculation needed to detect a treatment effect, defined as the difference in change scores in the muscle and mobility variables between the RENEW and usual care groups, with 90% power and an alpha level of 0.05 was 18 participants per group. The clinical database at the Huntsman Cancer Institute and the data warehouse at the University of Utah hospitals and clinics resulted in a pool of over 3000 patients from which we identified 286 cancer survivors who met the eligibility criteria related to age, diagnosis, and disease status. Each of these potential participants received a personal letter providing information about the study and a prompt to return a postcard to the study coordinator denoting no further contact be made regarding potential participation; 19% exercised this opt-out option. The 93 individuals responding to announcements were contacted directly via phone to assess their interest and screen for eligibility. All community ambulating males and females 60 years of age or older surviving cancer (breast, prostate, colorectal, lung or lymphoma), with no evidence of disease, and at least 6 months post-treatment (local = surgery and/or radiation; or systemic = chemotherapy; or a combination of local and systemic), and a Folstein Mini-Mental State Examination score > 23 were eligible. Participants were included if they had moderate levels (≥4 on a scale from 0-10) of fatigue and/or weakness as measured by the General Fatigue Scale and General Weakness Scale respectively. Those who met inclusion and were enrolled in the study also provided a list of comorbidities and their level of health related quality of life via a structured interview process and completion of the Short-Form 36 questionnaire respectively. Individuals were excluded if they had a central nervous system disorder (e.g., multiple sclerosis, Parkinson's disease), neurological insult (e.g., cerebrovascular accident), chronic fatigue syndrome, or myopathic or rheumatological disease that adversely impacts skeletal muscle structure/function or manifests in a mobility disorder. Engaging in regular (2-3 times per week) exercise (aerobic or resistance) during the preceding 6 months constituted another reason for exclusion.
The lower extremity RENEW exercise occurred on a recumbent eccentric stepper with a focus on the knee extensor (quadriceps) muscle group as previous studies [15–17] have noted clinically beneficial changes in the quadriceps with RENEW and positive relationships between quadriceps function and mobility in older individuals . An exercise specialist in a health science center-clinical setting supervised each participant's exercise session. Prior to training, the stepper seat setting was individually adjusted to each participant's leg length, and safety guidelines were reviewed. The recumbent eccentric stepper was powered by a 2-hp motor that drives the foot pedals in a "backward" direction (i.e., toward the individual). Eccentric muscle contractions occurred when the participant attempted to resist this motion by pushing on the pedals (with verbal instruction to "try to slow down the pedals") as the pedals moved toward the participant. Because the magnitude of the force produced by the stepper exceeded that of the participant's, the pedals continued to move toward the participant at a constant velocity (15-20 cycles per minute), resulting in eccentric contractions of the knee and hip extensors, including the quadriceps muscles (Figure 1).
The subjects began with thrice weekly, 3-5 minute sessions on the stepper for the first 2 weeks and progressed to a maximum of 15 minutes over the next 3 to 4 weeks and attempts were made to perform RENEW on the stepper for 16-20 minutes for the last 8 weeks. The progression of the eccentric exercise work rate was determined as a function of the perceived exertion (RPE) using a "target" workload on a computer monitor and is summarized in Table 1. Once the subjects achieved an RPE of "somewhat hard," they were instructed to maintain that RPE for the duration of the exercise program.
The Usual-Care group did not participate in the RENEW exercise program, but continued with their oncology follow-up care. Since the participants were cancer survivors this generally included a recommendation to call their oncologist or primary health care provider if any symptoms became problematic. Follow-up oncology appointments were at 6-month intervals and moved to annual visits after a year or two of continued remission.
Muscle Size: Quadriceps Lean Tissue
Muscle size (cm2), i.e., the average mid-thigh cross-sectional area (CSA) of lean skeletal muscle tissue of the quadriceps was determined using magnetic resonance image (MRI) of both thighs. Participants were placed supine in a 1.5 Tesla whole body MR imager (Signa Lightening LX 8.4; General Electric Medical Systems, Milwaukee, WI). To establish the region of interest (ROI), a coronal fast spoiled gradient echo scout scan was used to identify the superior and inferior boundaries of the scans (the femoral head and the tibiofemoral joint line). Once the ROI was established, axial T1 weighted images were acquired in the standard body coil using a fast-spin echo sequence with repetition time/time to echo = 550/9.2, 8-mm slice thickness, 15-mm interslice distance, and a 320 X 320 matrix. Four images from the middle 1/3 of each thigh were used to determine average CSA of lean tissue using custom written image analysis software (MatLab; Mathworks, Natick, MA). Manual tracing eliminated subcutaneous fat and bone and isolated the fascial border of the thigh to create a subfascial ROI. The total number of pixels within the ROI, a frequency distribution and a histogram of all pixels and signal intensities produced a specific peak designated as lean tissue. The same investigator, blinded to time point of the scan and slice location, performed measurements of individual participants before and after training. This technique has demonstrated high levels of intrarater reliability with an average interclass correlation coefficient of 0.99 and the validity of the measurement was determined by analysis of images obtained from a cadaveric thigh phantom .
Muscle Strength: Maximal Voluntary Isometric Knee Extension Peak Force
Knee extension peak strength (N) was quantitatively assessed by unilateral maximal voluntary isometric efforts on a KinCom dynamometer (Chattanooga Inc., Hixon, TN.). Both lower extremities were tested and these strength measures were assessed prior to and two-five days following the training interventions. Participants were seated and their knees were fixed at 90° of flexion and they were stabilized by chest and thigh straps. Participants were asked to fold their arms across their chest while performing these tests. Prior to testing, participants practiced submaximal contractions at 50% and 75% of their maximal effort. Three practice trials were then performed. After a brief rest period, three separate maximal contractions were performed, each held for 5 seconds with a 3-minute rest between trials. The outcome variable knee extension peak strength was calculated as the average of both lower extremity peak force trials. The test of isometric knee extension peak force with an isokinetic dynamometer machine has excellent reliability with ICCs > 0.99 .
Muscle Power: Stair Climbing Leg Power
Leg extension muscle power (W) was assessed with a simple, clinically-utilized timed stair climb power test . Stair climb leg muscle power was calculated with the following formula: power equals force times velocity. Stair climb time (s) and vertical height of the stairs (m) were used to calculate velocity (distance/time), and body mass (kg) and acceleration (m/s2) due to gravity were used to calculate force. At the base of a well-lighted, 10-stair flight participants were instructed to safely ascend the stairs as fast as they could when the examiner said, "Ready, set, go." Timing began once the participant began moving. When both feet of a participant reached the top step, the timing stopped. Time was recorded to the nearest 0.01 s, and the average of 3 trials was taken. The stair climb power measure is clinically relevant as it is associated with more complex modes of testing leg power impairments in older individuals (20) and the test-retest reliability is excellent with ICCs > 0.94 .
Mobility: Six-Minute Walk and Stair Descent Tests
The six-minute walk test, an assessment of mobility used to assess overall locomotion and endurance, measures the distance (m) walked in six minutes. Participants were asked to cover as much distance as possible within six minutes without running. The six-minute walk test has high test-retest reliability in older populations with various co-morbid conditions [22, 23].
The stair descent test of mobility relies almost exclusively on eccentric muscle contractions. Since mobility tasks requiring graded eccentric contractions are compromised more in old individuals than is the ability to perform concentric contractions while ascending stairs, impaired eccentric control may contribute to the greater number of falls during stair descent. Therefore, we employed the stair descent test of mobility by asking participants to descend one flight of stairs under close or contact supervision as quickly and safely as possible. Time was recorded to the nearest 0.01 second from a verbal go signal to final foot placement on a standard flight of 10 stairs and the average of three trials was recorded. Previous research has supported the high reliability of this measure of mobility with ICCs > 0.97 .
Data were analyzed with Sigma Stat Version 3.5 (Chicago, IL). Descriptive statistics were calculated for demographic variables and dependent measures. The assumptions of parametric statistical tests were assessed via tests of normality and homogeneity of variance. In all cases, the assumptions were met and therefore parametric tests were performed. In the analyses, we evaluated the effect of RENEW and Usual Care on muscle size, strength, power and mobility. First, pre-intervention baseline values for the dependent variables for RENEW and the Usual-Care groups were compared and tested with independent sample t-tests. Next, in order to control for potential pre-intervention differences between the groups, the primary aim was examined with a 2-way repeated-measures analysis of covariance (ANCOVA), with group (RENEW versus Usual-Care) as the between-subjects variable and time (Pre and Post intervention) as the within subject variable for each dependent variable: muscle size, strength, power and mobility. In all cases, the pre-intervention value for each dependent variable was used as the covariate. Because our hypotheses were focused on the differential response of the groups, our primary interest was the interaction between the group x time effects. In order to fully understand what changes drove any observed interaction effects or time main effects, and to examine and compare the magnitude of within group changes, interval estimators of pre to post intervention differences (95% confidence intervals of the mean differences) as well as calculation of within group effect sizes (ES) were utilized. The level of statistical significance for all tests for differences was set at p < 0.05.