Trial design
This study is a pilot, 2-arm, RCT. Between June 2013 and January 2015 a total of 20 patients at the university hospital Munich, Großhadern were randomly assigned to receive PRT (intervention group) or usual care (control group) during RT. Ethical clearance was obtained from institutional ethics committee (Project-Nr. 531–12) and written informed consent obtained from all participants before initiating study activities. Participants with a cancer diagnosis of the lung, pancreas, esophagus, head and neck, colon, rectum or anus were subsequently reviewed for inclusion and exclusion criteria. Study inclusion criteria were: (1) planned inpatient or outpatient RT, (2) ≥ 18 years of age, (3) diagnosed state of cachexia (weight loss greater than 5% over the past 6 months) or pre-cachexia (unintentional weight loss of 5% or less of usual body weight during the last 6 months). Patients with (1) metastatic disease, (2) severe neurological problems or other contraindications for the PRT were excluded. The project coordinator screened potential participants for eligibility via MOSAIQ®-Software (Radiation Oncology Information System). This software manages the aspects of the radiation oncology program and collects all information of the patients and makes them accessible. Study information sheets were sent to patients in the form of invitation letters. Participants who met the diagnosed tumor localization were met at the time of computer tomography-planning to explain the study, screen again for eligibility, and obtain informed consent. Registered participants were planned for baseline assessment. Participants were allocated at random to the control or exercise group via blocked randomization in sealed envelopes.
Baseline data for all participants were ascertained via medical records and patient interview. This included demographic information, UICC-status (Union internationale contre le cancer, tumor staging system), comorbidities and the results of blood samples. One study coordinator completed all assessments to enhance patient compliance. Body weight loss percentage was calculated via the individuals’ body weight 6 months before (in retrospect) and the current body weight. Participants completed two questionnaires: The Multidimensional Fatigue Inventory (MFI) [
31] which consists of 20 items that measure subgroups (general, physical and mental fatigue as well as reduced motivation and reduced activity) of fatigue with a 5-point Likert scale and the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire [
32,
33] which registers well-being for physical, social/family, emotional and functional aspects of quality of life and additional concerns in cachexia with 5-point Likert scale for 39 items. To measure physical performance the Six-Minute Walk Test (6MWT) [
34] was applied. This assessment instrument includes walking distance as well as heart rate, pulse oximetry (Contec Medical Systems CO., Ltd., Model: CMS50E), fatigue (with a rating of perceived exertion (RPE) from 0 to 10) and dyspnea (RPE 0–10) before and after the test. To document changes in muscle force, strength of the functional muscle group for elbow flexion in supine position as well as of knee extension in sitting position (in each case right and left) was tested via hand-held dynamometry (Mecmesin Ltd., Broadbridge Heath, West Sussex, RH12 3IR, UK) for isometric maximal muscle strength [
35]. Bioelectrical impedance analysis (BIA; AKERN SRL, BIA 101 New Edition) was executed to assess the adaption in body composition [
36]. Patients were lying supine on a therapy table. The measurements took place at the right side of the body with the tetrapolar-technique of 4 standard electrodes on the surface of the hand and the foot. Constant frequency of 50 kHz and 400 μA constant current in electrical resistance of the body were used to measure resistance and reactance. The above mentioned assessments were carried out at baseline (t1), after 7 weeks of radiotherapy (t2) and 8 weeks after radiotherapy (t3).
Before each training session the current condition of the patient was accurately gathered. This included communication with the responsible nurse and/or physician about the ongoing state, including the results of the latest investigations such as blood pressure, temperature and laboratory investigations. As a last safety action the patient was asked if he felt able to carry out the training. Heart rate during training was monitored by a chest strap that sends the current heart rate by a radio signal to a wristwatch. It was payed attention that the participant’s heart rate never exceeded the maximum heart rate measured during the 6MWT and that the heart rate became slower in the breaks during the sets and the changes to another exercise machine. After the training each inpatient was personally carried back to the ward and asked for any complaints. Furthermore, the responsible nurse and/or physician were informed about the patients return to the ward and any noticeable situations during the training.
The exercise intervention was undertaken in the hospitals department of physical and rehabilitation medicine and based on standardized but individualized training protocols. All exercises were carried out within the individuals given limb range of motion and in a dynamic way without defined execution time for the concentric and eccentric phase. Goal of the very first training was to determine the training load set for hypertrophic adaption. Because of the vulnerable patient group a submaximal step by step approach within 3 sets and 8–12 repetitions was chosen. The first two sets acted as both muscular and movement adaption. The last set served as submaximal one-repetition maximum estimation. The evaluation of the training prescription was done in real-time by a supervising physiotherapist.
The training protocol consisted of a warm up period for 5 min on a bicycle ergometer or an upper body cycle with individual selectable wattage. A leg press, a latissimus pull-down and a chest press (Kaphingst) formed the three equipment supported core exercises. All exercises were performed with 8–12 repetitions and 3 sets. After each set and during the changes to another exercise machine a break of maximum 60 s was assured. After each machine the patients rated their perceived exertion from 0 to 10. The weight loading was increased at the next workout if RPE < 7. For the two upper limbs exercise a progression of 2.5 kg weight loading and for the lower limbs exercise a progression of 5.0 kg weight loading was implemented. The exercises were supervised all the time for performance and safety reasons by physiotherapists experienced in oncology rehabilitation and certified in medical training therapy.
For exercise participants with concomitant chemotherapy to their RT protocol timing for the training intervention was organized e.g. between the changes of 24 h constant-rate infusion. In the rare cases where this was not possible the exercise intervention was adjusted in order to protect the peripheral venous catheter in the Vena mediana cubiti by limiting an exercise in the range of motion or by replacing the two upper body machine supported exercises by: low pulley seated bench cable crossover and low pulley lateral extensions because of the almost static elbow angulation.
The control group received usual care. This could include inpatient physiotherapy if prescribed by the ward physician. Muscle strengthening techniques were not part of the usual care.