Perioperative rehabilitation in operation for lung cancer (PROLUCA) – rationale and design

The home-based exercise program is individually designed for each of the participants randomized to a preoperative intervention. The ultimate goal of the preoperative home-based exercise program is to ensure that the patients perform cardiovascular exercise of moderate-vigorous intensity (~60-80% of maximum heart rate (HRmax)) for at least 30 minutes every day until surgery. The preoperative period varies in length and the intention is not to exceed 14 days. The preoperative exercise is monitored by a heart rate sensor (Polar Team 2 System, with off-line transmitters) and an exercise diary logbook.

The postoperative intervention consists of a supervised 12-week rehabilitation program containing 24 group-based exercise sessions, three individual counseling sessions, and three group-based lessons in health-promoting behavior. If the participants have special needs in terms of smoking cessation, nutritional counseling or patient education, this is offered too.

The postoperative physical exercise consists of an individually prepared supervised strength exercise – and a group-based cardiovascular exercise twice a week (60 minutes/session) on non-consecutive days for 12 weeks, a total of 24 sessions, containing the following elements:

Warm-up (five minutes) and cardiovascular exercise (25 minutes) on ergometer bike (BODY BIKE Classic Supreme©), individually prepared strength exercise (25 minutes) carried out using five machines (Technogym™), leg press, chest press, leg extension, pull to chest, pull-down (upper body). The practical aim of strength exercise is to complete three series of 5–12 sets. Trained physiotherapists and cancer nurse specialists supervise the training program following the recommended principles [50]. All exercise sessions will include supervised breathing exercises combined with stretching and relaxation techniques (five minutes). All the cardiorespiratory exercise is designed such that participants begin exercising at a low intensity (~50%-60% of individually determined HRmax) which is subsequently increased to more moderate to vigorous intensity (~70%-80% of individually determined HRmax). The ultimate goal for the postoperative exercise is two group-based exercise sessions per week, with a cardiorespiratory intensity for the first four weeks at ~50-60% of individual HRmax. The next eight weeks the intensity increases to moderate-high intensity at ~70-90% of individually determined HRmax. The heart rate will be monitored continuously throughout the cardiorespiratory exercise using heart rate monitors and software (Polar Team² Pro©). All interventions will be individually tailored to each participant and following the principles of aerobic or resistance training prescription guidelines for adults as recommended by the American College of Sports Medicine (ACSM) [50]. The ultimate goal for the strength exercise program is to exercise with an intensity of ~60-80% of 1 RM two times a week for 12 weeks. To ensure progression every second week, the load is progressively increased and the number of repetitions are reduced starting out at 12 repetitions in three sets progressing to 10 repetitions in three sets to a final of eight repetitions in three sets. The progression is documented in a study exercise log file for registration of the intensity of all sessions along with data on blood pressure prior to exercise.

To maximize adherence, several strategies will be employed including telephone-based follow-ups. The patients are provided free parking in front of the center and transport expenses are covered. The high degree of scheduling flexibility allows participants to perform test at a convenient time and work around other competing demands such as medical appointments, work, and family commitments.

VO₂peak is evaluated by an incremental test using an electromagnetically braked cycle ergometer (Lode Corival Ergometer©). Inspired and expired gases are analyzed breath-by-breath by a metabolic cart (JAEGER MasterScreen CPX©). Subjects begin pedaling at seven watts and resistance increases after a predefined 10 watts ramp protocol until exhaustion or a symptom-limited VO₂peak is achieved (pain, dizziness, anxiety etc.). This regimen has previously been demonstrated to be appropriate for measuring VO₂peak in prior studies in patients with ankylosing spondylitis [51]. Other similar VO_2peak protocols are found appropriate for measuring VO₂peak in NSCLC [38, 39, 52].

Patient-reported outcomes (PROs) PROs will include HRQoL, symptoms and side effects, anxiety and depression, well-being, distress, lifestyle, sickness absence, work status, and social support. HRQoL is assessed using the integrated system of the European Organization for Research and Treatment in Cancer (EORTC) for assessing the HRQoL of cancer patients participating in international clinical trials and devised through collaborative research. The EORTC QLQ-C30 assesses patient symptoms and HRQoL in lung cancer patients [53]. Symptoms and side effects will be assessed using the EORTC–LC13, which is an additional page to the EORTC-QLQ specifically designed to cover a wide range of lung cancer patients varying in disease stage and treatment modality [54]. EORTC measures single items and the scales range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status/quality of life represents a high HRQoL. However, a high score for a symptom scale/item represents a high level of symptomatology or problems [53, 54].

HRQoL will also be assessed using the Functional Assessment of Cancer Therapy - Lung (FACT-L) scale that contains four subscales for physical (7-items), functional (7-items), emotional (6-items), social/family well-being (7-items) plus a lung cancer specific subscale (15-items) which will be summed to obtain the FACT-L score (all 42 items) [55].

General well-being is assessed using the 36-Item Short Form Health Survey (SF-36), standard recall (four weeks). The SF-36 includes eight scales measuring general health with two summary scales; physical and mental component scales [56, 57]. To assess psychological well-being, the Hospital Anxiety and Depression Scale (HADS) with 14 items will be administered, designed to measure general anxiety and depression for use in investigations of patients with physical illness [58]. The distress thermometer is a validated measure of distress and consists of a single item, with responses ranging from 0 to 10 [59].

The Multidimensional Scale of Perceived Social support (MSPSS) is a 12-item scale assessing social support. Each item is answered on a seven-point Likert scale, from one: Very strongly disagree, to seven: Very strongly agree. The scale yields three subscale scores, for Family, Friends, and Significant Others, and a Total score, which is confirmed in a confirmatory factor analysis [60]. In other different cancer studies, all the above-mentioned validated instruments were found appropriate and easy to administer [35, 52, 59, 61].

Physiological measurements will include: (1) functional capacity, (2) pulmonary function, (3) cardiovascular O₂ delivery, and (4) muscle strength. (1) functional capacity will be measured by a six-minute walking distance (6MWD) test carried out over a pre-measured distance of 22 m and in accordance with the American Thoracic Society (ATS) statement [62]. The 6MWD test has demonstrated good reliability and validity in patients with chronic obstructive lung disease [63], a patient group with similar symptomatology and pathophysiology. (2) Pulmonary Function will be determined by assessing the Forced Expiratory Volume in one second (FEV₁), and the FEV₁% which is the ratio of FEV₁ to the Forced Vital Capacity (FVC) using a Triple V digital volume sensor© connected to JAEGER MasterScreen CPX©. All pulmonary function tests will be performed in a standing position and according to the ATS guidelines [48]. (3) Arterial O₂ Saturation will be assessed at rest and continuously during exercise using pulse oximetry (Nellcor, OxiMax N-65©), which provides the most accurate non-invasive assessment of blood arterial O₂ saturation levels. Muscle strength is measured by 1RM [64] using machines (Technogym™) that includes leg press (lower extremity) and chest press (pectoral muscles).

In all patients lung cancer subtype, stage and extent of surgery will be related to the effect of exercise and rehabilitation interventions.

Tracking and monitoring of adverse events are assessed as follows: (1) before every intervention- and test-session, all patients will receive face-to-face supervision by a specialized trained cancer nurse discussing any potential negative side effects of the intervention assignment. All injuries and adverse events (e.g., knee pain, back pain) will be recorded as unintended events. In addition, heart rate and blood pressure are recorded prior to every intervention session and repeated if any adverse events should occur during exercise.

This randomized phase II trial will accrue 380 subjects with operable NSCLC over an accrual period of ~2 years. The present design consists of four intervention groups of equal size, and it is assumed that no interaction occurs between the groups. With the smallest clinical relevant difference set at 2 mLO₂ ^. kg^{-1 .} min^-1,95 participants are required in each group (power: 80%), giving a total inclusion of 380 patients.

For each of the primary and secondary endpoints, three separate t-tests will be used to compare each experimental arm to the control arm in mean change across time of the endpoint. For each endpoint, the overall alpha level will be controlled at a two-sided 0.05 by using Holm's procedure [65]. That is, Holm's procedure first ranks the three p-values from lowest to highest. The first (lowest) p-value has to be less than 0.05/3 (0.0167) to be significant and permit continuation to the other t-tests. The Holm's procedure continues sequentially in this fashion using alpha levels of 0.05/2 (0.025) and 0.05/1 (0.05) for the remaining two t-tests, respectively. Power for this study is defined as the probability that at least one of the three t-tests of the arm effect on VO₂peak is significant; in other words, power is the probability that the first of the 3 ordered t-tests are significant. We assume that change in VO₂peak will have a standard deviation of 4.0 mL ^. kg^{-1 .} min^-1 as observed in previous research [27, 36]. Statistical power depends upon the configuration of mean change in VO₂peak across the 4 arms. Thus, for example, 80% power is obtained when the mean change in VO₂peak across Arms 1, 2, 3, and 4 is 0.60, 0.60, 2.10, and 0.0 (mL ^. kg^{-1 .} min^-1), respectively.

The intention-to-treat analysis includes all randomized participants in their randomly assigned allocations. The intervention group assignment will not be altered based on the participant's adherence to the randomly allocated study arm. Patients who are lost-to-follow-up are included in the analysis (intention to treat). For the primary analysis, a multiple regression model will be used to assess a change in VO₂peak on study group, the baseline value of the endpoint, and other pertinent baseline variables that may influence change in the study endpoints (e.g., co-morbid conditions/medications, self-reported exercise history, age). Data from PROs will be presented as mean, standard deviation (SD), median and inter-quartile range (IQR) and all change scores (value at follow-up minus value at baseline) will be presented with a 95% confidence interval.