EffectiveNess of a multimodal preHAbilitation program in patieNts with bladder canCEr undergoing cystectomy. The ENHANCE randomized controlled trial.

In the Netherlands annually around 6500 patients are diagnosed with bladder
cancer. About 20-30% has muscle invasive disease for which radical cystectomy
(RC) is an established effective treatment. RC is also the treatment of choice
in case of a high-risk tumor and in intravesical chemotherapy refractory
bladder cancer. RC is a challenging and costly surgical procedure and results
in 50-65% of patients experiencing perioperative complications of which 10-20%
are high-grade. Bladder cancer patients often have poor levels of
cardiorespiratory fitness, are malnourished, and smoke. This poor fitness and
nutritional status may be exacerbated by neoadjuvant chemotherapy. At the same
time, low fitness, malnutrition, smoking, as well as experiencing of anxiety
and/or depression before surgery are related to the occurrence of perioperative
complications and longer length of hospital stay, leading to higher medical
costs. The potential value of a multimodal preoperative psychological
counseling in these patients has been understudied and no adequately powered
trial has been performed to establish its effectiveness in reducing morbidity
and costs.

To study the effectiveness of a multimodal prehabilitation program preceding
radical cystectomy in reducing the number and severity of perioperative
complications within 90 days, shortening the length of hospitalization and
reducing the number of readmissions. Furthermore, we will investigate the
effects of the prehabilitation program on physical fitness, muscle strength,
physical functioning, nutritional status, smoking behaviour, anxiety and
depression, fatigue, quality of life, physical activity, tumor tissue
characteristics, and healthcare costs.

A multicenter randomized controlled trial.

Patients will be randomized to either an intervention group or to a usual care
control group (1:1 allocation). The intervention group will receive a
structured multimodal prehabilitation program consisting of a tailored exercise
program, nutritional intervention and if relevant smoking cessation and/or
psychological counseling. The exercise program is designed to maximize
improvement in cardiorespiratory fitness and decrease anxiety and depression
within a short timeframe (approximately 3-6 weeks). The intervention consists
of a 3 times weekly individually tailored supervised aerobic training (3x/week,
resistance training (2x/week) and relaxation exercises (1x/week). Additional
instructions for exercising and relaxation at home will be provided. For
patients who receive neo-adjuvant chemotherapy treatment, the intervention
consists of a 2 times weekly supervised aerobic training combined with
resistance exercises during chemotherapy treatment. Similar programs have been
demonstrated to be both feasible and effective in a number of older and
vulnerable patient populations. Nutritional counseling will be provided by a
dietician, including tailored dietary advice aiming at a total protein intake
of 1.9 (- max 2.3) g/kg fat free mass per day and a minimum of 25-30 g
protein/meal. In addition, patients will be provided with a supplement
containing 30 g of protein, 20 microgram of vitamin D and 250 mg of calcium
immediately after supervised training and daily in the morning after waking up
or before sleep. Smoking cessation assistance will be provided by intensive
in-person counseling and telephone follow-up, and nicotine replacement therapy.
The smoking cessation program will involve intensive in-person counseling,
telephone follow-up, and nicotine replacement therapy. Patients who screen
positive for clinically relevant levels of anxiety and/or depression will be
referred to an appropriate medical health professional (i.e., social worker,
psychologist or psychiatrist).

Participating in the study requires time for the measurements (all patients)
and for the training and supervision with regard to nutrition and possible
smoking cessation and/or psychological consultation (patients in the
intervention group). Patients who start exercising can also experience the
normal effects of exercise such as temporary fatigue or muscle pain.