Design and setting
The study was conducted as a single-center, prospective feasibility study with eight patients undergoing multimodal prehabilitation prior to surgery for colorectal cancer. Patients were recruited from the Department of Surgery, Zealand University Hospital, Roskilde, Denmark between October 4th, 2018, and January the 14th 2019. The intervention was planned in three standardized individualized intervention components: Training intervention, Diet and Nutritional support, and medical optimization. All interventions were protocolled before the initiation of the study. A graphic description of the course of the intervention and testing can be seen in Fig. 1.
All patients received standard perioperative care, including a multi-disciplinary team conference, preoperative lung exercise education with positive expiratory pressure whistle, protein-enriched high-energy supplements 5 days prior to surgery, carbohydrate loading prior to surgery, and full enhanced recovery after surgery[11, 12]. Certified colorectal surgeons performed the surgeries.
Participants eligibility
All patients with WHO performance status I or II, with planned surgery for colon or rectal cancer, without neoadjuvant radio- or chemotherapy were eligible for the study. Patients were excluded if they were planned for abdominoperianeal resection, serum creatinine > 250 mmol/L, not able to understand or write Danish, had severe cognitive deficit (Mini-Mental State Examination < 11[13]), not able to perform exercise, known metastatic disease, or withdrew consent.
The rationale for using WHO performance status as a screening tool
In Denmark, the government has introduced a cancer treatment guarantee, which means that patients are to undergo surgery within a maximum of 14 days from diagnosis to surgery. This study was approved to postpone the surgery for high-risk patients with potentially modifiable risk factors. Therefore, patients had to be assessed for eligibility shortly after referral to make sure that no patients had postponed surgery unless they were included in the study. For the majority of patients, WHO performance status has been rated at referral, and have good inter-observer reliability[14, 15] which made it the most optimal available tool for screening. We chose to include patients with WHO performance status I and II, but not III or IV since these patients rarely are planned for surgery and were expected not to be able to perform the planned training intervention.
Intervention
Training intervention
The training intervention consisted of High-Intensity Interval Training (HIIT) and resistance training in supervised individual training sessions of approximately one-hour duration 3 times a week for at least 4 weeks. The HIIT was performed on an exercise bike and consisted of 4 minutes warm-up, followed by 4 bouts of 2 minutes at an intensity > 90% of the participants' maximum heart. Between and after the bouts, low load intervals of a duration of 4 minutes was performed. Heart rate was continuously monitored by a chest-worn monitor (Polar A300®, Polar Electro, Finland). The threshold of 90% of the maximum heart rate was determined by a Cardiopulmonary Exercise Test (CPET) in each participant. The participant was able to adjust the load, with the physiotherapist encouraging the participant to obtain the > 90% of maximum heart rate during the bouts. After each bout and at the end of the HIIT training the participant was asked to rate self-exertion using the Borg RPE 6–20 scale[16]. After the HIIT session, resistance training was performed using machines (Technogym®, Italy) in the following order; chest press, lateral pulldown, and leg press. Three sets of 8–12 repetitions were performed in each machine. An 8-repetition maximum test (8-RM)[17] was used to calculate 1-RM. Resistance was set to progress throughout the intervention using the following model; week 1 (65% of 1-RM), week 2 (70% of 1-RM), week 3, 4, and 5 (75% of 1-RM). Beside HIIT and resistance training the patients were encouraged to perform light to medium aerobic exercise for at least 30 minutes a day at home. This was not supervised or registered.
Dietary and nutritional intervention
The nutritional intervention consisted of an addition of 0.4 g/kg bodyweight protein two times a day by TMP-90 Shake® (Friesland Campina, Netherlands) regardless of nutritional status or weight loss. One dose taken just after exercise or training, and one before sleep. In addition, a multivitamin tablet (Apovit Multi®, Apovit, Denmark) with 100% of the daily recommended dosage, and a D-vitamin with calcium tablet (38 µ + 400 Unikalk Mega®, Orkla Health A/S, Denmark) was taken daily. The dietary intervention consisted of an interview with a dietician within the first week after baseline testing. Estimation of current intake was done by a 24-hour food recall and daily dietary needs were conducted by estimation of base protein and total energy requirements by Harris-Benedict equation[18], with an added factor of 1.3–1.5, depending on the individual physical activity level. Patients were then advised how to change their diet to meet the excess demand for energy and protein, and if necessary instructed in using additional protein and energy drinks.
Medical optimization
The principal investigator performed medical optimization as part of the baseline testing and interview. Expanded routine blood work was performed including anemia parameters, hemoglobin A1c, cholesterol, vitamin status, minerals, white blood cell count, liver, and kidney parameters. If any unknown or poorly regulated disease was suspected, the patient was either referred to a specialist or adjusted in the medication, depending on the issue. Anemia needing correction was defined as ≤ 11.3 g/dL for both men and women, and patients were referred to intravenous administered Iron(III)isomaltoside (Monofer® Pharmacosmos A/S, Denmark) at the earliest convenience. Medical history was assessed and current medication was inspected for possible seponation or dose reduction. Patients with a high-risk intake of alcohol or smokers were encouraged to quit, and if interested referred to the in-hospital alcohol and tobacco cessation course.
The complete intervention described in protocols translated into English can be found in the supplementary material (Appendix 1–3). Full reporting of the training intervention in regards to Consensus on Exercise Reporting Template (CERT) guidelines[19] for reporting exercise interventions can be found in the supplementary material (Appendix 4).
Primary outcomes
The primary outcome was changes in maximum oxygen intake (VO2 peak) between baseline and preoperative assessment by CPET. VO2peak was estimated at the maximum oxygen uptake/min/kg body weight. Previous studies on repeated CPET´s have found a biological variation of VO2peak on 3.9% and an analytic variation of 2.2%[20]. Non-responders were defined as having an increase of less than 5% in VO2 peak. Further, the time spent above 90% of maximum heart rate during HIIT was of primary interest as a measurement of per-protocol compliance. Total time spent above 90% of maximum heart rate during HIIT was measured for each training session and each bout. We considered complete training as a minimum of 4 minutes of training above > 90% of maximum heart rate and with a Borg’s RPE > 16 and was used as goal of compliance. The percentage of completed training sessions was used as the measurement of adherence.
Secondary outcomes
Secondary outcomes were: change in maximum wattage during CPET, muscle strength, functional capacity, body weight, albumin, compliance with the dietary and nutritional intervention, adverse events during the intervention, postoperative length of stay, and complications within 30 days after surgery.
Other variables
Completion of the nutritional support was defined as ≥ 65% of both protein and vitamin ingestion. Patients received a fixed amount of protein supplement at baseline and the day prior to surgery the residual supplement was measured and usage was calculated as a percentage of the required intake. WHO performance status and ASA score were estimated by the surgeon at the first visit in the outpatient visit. Charlson comorbidity score was calculated including tumor and age[21]. Frailty was determined by a least one positive criteria on Fried frailty [22, 23] or by a Geriatric-8 (G8) score < 14[24]. Discharge was managed through standardized discharge criteria. Recording of adverse events and postoperative complications were performed by an external assessor through medical records and graded by both the Clavien-Dindo classification[25] and the Comprehensive Complication Index[26]. Any readmission and Days at Home within 30 days after surgery (DAH-30)[27] was asses through entries in medical records.
Testing
Testing was performed at baseline, the day prior to surgery, and four weeks after surgery. Testing included Cardiopulmonary Exercise Test (CPET) and five physical function tests: Handgrip strength, Isometric leg extension strength test[28], 6 minutes walk test, 30 sec. Sit to stand test[29], and 30 sec. stair climb test, in this exact order. The principal investigator performed all baseline testing. Pre- and postoperative testing (a day prior to surgery and four weeks after surgery) was performed by a physiotherapist specially trained to perform the testing procedures. CPET was performed on Jaeger® Vyntus® CPX (CareFusion, San Diego, US) by steep ramp until exhaustion, with an expected testing time of 8–12 minutes. Handgrip strength was measured using a hand dynamometer (Jamar Smart®, Patterson Medical, Saint Paul, Minnesota, US) with three measurements on each hand, starting with the left hand. Isometric leg extension strength test was performed with a Lafayette Manual Muscle Tester (model LIC.01165, Lafayette Instrument Company, Lafayette, IN US) with three measurements on each leg, starting with the left leg. 6-minutes walk test was performed in an undisturbed hallway on a 20 meters course. Sit to stand was performed as described by Jones et al[30]. Stair climb test was performed in an undisturbed stairwell with 10 steps of 17 cm´s on each floor, with a maximum of twelve floors available. The number of steps achieved within 30 seconds was recorded. Test of strength for chest press, lateral pull-down, and leg press was conducted as an 8-RM test and a 1-RM calculated from Brzyckis formula[31]. Anthropometric measurements including skin fold, circumference, weight, and height were performed together with Patient-Generated Subjective Global Assessment (PG-SGA)[32] which was used for nutritional screening. Frailty was assessed by both G8 score and Fried frailty[23] at baseline.
Statistics and reporting
No statistical analyses were performed. Reporting was conducted in adherence with the CONSORT statement for feasibility and pilot studies[33].