EffectiveNess of a Multimodal preHAbilitation Program in patieNts With Bladder canCEr Undergoing Cystectomy (ENHANCE)

EffectiveNess of a Multimodal preHAbilitation Program in patieNts With Bladder canCEr Undergoing Cystectomy. The ENHANCE Randomized Controlled Trial

Currently, the potential value of a multimodal prehabilitation program in bladder cancer has not been extensively studied. The investigators designed the ENHANCE study to assess the effect of a structured multimodal prehabilitation program in 154 patients with bladder cancer on the number (primary endpoint) and severity of complications within 90 days, length of hospital stay, readmissions, 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.

Study Overview

• Status: Recruiting
• Conditions: Bladder Carcinoma
• Intervention / Treatment: Behavioral: Prehabilitation

Detailed Description

The ENHANCE study is a multicenter, randomized controlled trial. The intervention group will participate in a prehabilitation program of 4-6 weeks before surgery, and additionally during neoadjuvant chemotherapy if applicable. The prehabilitation program consist of a tailored exercise program, nutritional support and if relevant smoking cessation and/or psychological counselling. The exercise program is under supervision of an oncology specialized physiotherapist and comprises aerobic-, resistance- and breathing- and relaxation exercises. Patients will be asked to be physically active for an additional 2 times a week for at least 30 minutes. A dietician will provide nutritional support and give dietary advice to increase protein intake to enhance the anabolic effect on muscle mass. Additionally, patients will receive a supplement containing 30 g of high quality whey-protein daily preferably before sleep and after the supervised training. Patients who score high on anxiety and depression will be offered a referral to a psychological support. Intensive counselling and nicotine replacement therapy will be offered to all patients who smoke. Patients in the intervention group will be asked to keep a diary to track unsupervised activity and to track intake of the protein supplementation. The physical activity level in both groups will be obtained via questionnaire.

• Study Type: Interventional
• Enrollment (Anticipated): 154
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Martijn Stuiver, PhD; Phone Number: +31205124136; Email: m.stuiver@nki.nl
• Study Contact Backup: Name: Emine Akdemir, MSc; Phone Number: +31683395101; Email: e.akdemir@nki.nl

Study Locations

• Netherlands
  • Doctor Molewaterplein 40
    • Rotterdam, Doctor Molewaterplein 40, Netherlands, 3015 GD
      • Recruiting
      • Erasmus Medical Center
      • Contact: Joost Boormans
  • Geert Grooteplein Zuid 10
    • Nijmegen, Geert Grooteplein Zuid 10, Netherlands, 6525 GA
      • Recruiting
      • Radboudumc
      • Contact: Toine van der Heijden
  • Hanzeplein 1
    • Groningen, Hanzeplein 1, Netherlands, 9713 GZ
      • Recruiting
      • UMC Groningen
      • Contact: Annemarie Leliveld
  • Heidelberglaan 100
    • Utrecht, Heidelberglaan 100, Netherlands, 3584 CX
      • Recruiting
      • UMC Utrecht
      • Contact: Anne M. May, Prof. dr.; Email: a.m.may@umcutrecht.nl
  • Michelangelolaan 2
    • Eindhoven, Michelangelolaan 2, Netherlands, 5623 EJ
      • Recruiting
      • Catharina Ziekenhuis
      • Contact: Evert Koldewijn
  • P. Debyelaan 25
    • Maastricht, P. Debyelaan 25, Netherlands, 6229 HX
      • Recruiting
      • Maastricht UMC+
      • Contact: Bart Bongers
  • Wagnerlaan 55
    • Arnhem, Wagnerlaan 55, Netherlands, 6815 AD
      • Recruiting
      • Rijnstate
      • Contact: Carl Wijburg
  • Wilhelminalaan 12
    • Alkmaar, Wilhelminalaan 12, Netherlands, 1815 JD
      • Recruiting
      • Noordwest Ziekenhuisgroep
      • Contact: Siebe Bos

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed, primary, bladder cancer (cTa-4N0/N+M0),
• Planned to undergo radical cystectomy,
• Age ≥ 18 years.

Exclusion Criteria:

• Subjects with severe cognitive or psychiatric disorders,
• Subjects who are operated within 3 weeks,
• Subjects with insufficient command of the Dutch language, which precludes them from following study instructions or completing study questionnaires,
• Subjects who have contraindications to safely perform exercise training or testing (i.e., CPET),
• Subject who are unable or unwilling to participate in the intervention.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prehabilitation group; The intervention group will participate in a prehabilitation program of approximately 4-6 weeks before surgery, and additionally during neoadjuvant chemotherapy if applicable. The program consist of a tailored exercise program, nutritional support and if relevant smoking cessation and/or psychological counselling. The exercise program is under supervision of an oncology specialized physiotherapist and comprises aerobic-, resistance- and breathing- and relaxation exercises. A dietician will provide nutritional support and give dietary advice to increase protein intake, including a supplement containing 30 g of whey-protein daily and after supervised training. Patients who score high on anxiety and depression will be offered a referral to a psychologist. Intensive counselling and nicotine replacement therapy will be offered to all patients who smoke. Patients will be asked to keep a diary to track unsupervised activity and to track intake of the protein supplementation.	Behavioral: Prehabilitation; Multimodal prehabilitation program
No Intervention: Control group; Patients randomized to the control group will receive care as usual according to local ERAS guideline implementation. In addition, they will receive a leaflet with the recent guidelines regarding physical activity, dietary advice, and smoking cessation. Their actual physical activity level will be obtained via questionnaire.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complications	The proportion of patients having Clavien-Dindo grade 2 or higher perioperative complications; obtained from the medical records	0-12 weeks post-surgery (measured 4 weeks and 12 weeks post-surgery)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
High grade complications	Clavien Dindo grade 3 or higher	0-12 weeks post-surgery
Duration of hospital stay	Time from admission until hospital discharge	0-12 weeks post-surgery
Readmissions	Hospital readmission as recorded in medical file	0-12 weeks post-surgery
Disease status	Progression/recurrence, any additional treatment as recorded in medical file	0-12 weeks post-surgery
Change in cardiorespiratory fitness	Assessed via cardiopulmonary exercise test (CPET)	T0a (baseline), T1 (within 1 week before surgery)
Change in muscle strength	Grip strength	T0a (baseline), T1 (within 1 week before surgery), T3 (12 weeks post-surgery)
Change in muscle strength	30s chair stands	T0a (baseline), T1 (within 1 week before surgery), T3 (12 weeks post-surgery)
Change in physical performance	Short Physical Performance Battery (SPPB)	T0a (baseline), T1 (within 1 week before surgery), T3 (12 weeks post-surgery)
Change in nutritional status	Short Form- Patient Generated Subjective Global Assessment (SF-PGSA)	T0a (baseline), T1 (within 1 week before surgery), T3 (12 weeks post-surgery)
Change in body composition	Fat free mass and fat mass assessed by Scale Bioelectrical Impedance Analysis (BIA)	T0a (baseline), T1 (within 1 week before surgery), T3 (12 weeks post-surgery)
Nil per mouth consumption during hospitalization	The total days as recorded in medical file	0-12 weeks post-surgery
Change in weight	Measured in KG	T0a (baseline), T1 (within 1 week before surgery), T3 (12 weeks post-surgery)
Height	Measured in cm	T0a (baseline) - T3 (12 weeks post-surgery)
Change in smoking status	Self-developed questionnaire	T0a (baseline), T0b (if applicable: after neoadjuvant chemotherapy), T1 (within 1 week before surgery), T2 (4 weeks post-surgery), T3 (12 weeks post-surgery)
Sense of coherence (SOC)	13-item SOC questionnaire	T0a (baseline)
Change in fatigue	MFI questionnaire	T0a (baseline), T0b (if applicable: after neoadjuvant chemotherapy), T1 (within 1 week before surgery), T2 (4 weeks post-surgery), T3 (12 weeks post-surgery)
Change in HRQoL	EORTC QLQ-C30	T0a (baseline), T0b (if applicable: after neoadjuvant chemotherapy), T1 (within 1 week before surgery), T2 (4 weeks post-surgery), T3 (12 weeks post-surgery)
Change in muscle invasive bladder cancer specific scores	EORTC QLQ-BLM30	T0a (baseline), T0b (if applicable: after neoadjuvant chemotherapy), T1 (within 1 week before surgery), T2 (4 weeks post-surgery), T3 (12 weeks post-surgery)
Change in health status	EQ-5D-5L	T0a (baseline), T0b (if applicable: after neoadjuvant chemotherapy), T1 (within 1 week before surgery), T2 (4 weeks post-surgery), T3 (12 weeks post-surgery)
Change in physical activity	SQUASH questionnaire	T0a (baseline), T0b (if applicable: after neoadjuvant chemotherapy), T1 (within 1 week before surgery), T2 (4 weeks post-surgery), T3 (12 weeks post-surgery)
Change in anxiety and depression	HADS questionnaire	T0a (baseline), T0b (if applicable: after neoadjuvant chemotherapy), T1 (within 1 week before surgery), T2 (4 weeks post-surgery), T3 (12 weeks post-surgery)
Intervention costs	Cost analysis	T0a (baseline) - T3 (12 weeks post-surgery)
Healthcare resources consumption	Medical Consumption Questionnaire (iMCQ)	T0a (baseline) - T3 (12 weeks post-surgery) (measured within 1 week before surgery, 4 and 12 weeks post-surgery and if applicable : after neoadjuvant chemotherapy)
Work status	Productivity Cost Questionnaire (iPCQ)	T0a (baseline) - T3 (12 weeks post-surgery)
Satisfaction with prehabilitation in intervention group and evaluation in control group	Self-developed questionnaire	T3 (12 weeks post-surgery)
Non participation analysis	Identify clinical and sociodemographic variables that are related to non-participation of patients in this trial via questionnaire	T0a (baseline)
Hypoxia	To study the effectiveness of the prehabilitation program in terms of inducing favorable changes in tumor hypoxia markers	T3 (12 weeks post-surgery)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall and bladder-cancer specific survival	Exploratory outcome	0-60 months
Progression-free survival	Exploratory outcome	0-60 months

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Karolinska Institutet; Radboud University Medical Center; University Medical Center Groningen; Maastricht University Medical Center; UMC Utrecht; Erasmus Medical Center; Noordwest Ziekenhuisgroep; Rijnstate Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2022
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): October 1, 2025

Study Registration Dates

• First Submitted: July 14, 2022
• First Submitted That Met QC Criteria: July 27, 2022
• First Posted (Actual): July 29, 2022

Study Record Updates

• Last Update Posted (Actual): October 31, 2022
• Last Update Submitted That Met QC Criteria: October 27, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: exercise; smoking cessation; bladder cancer; prehabilitation; surgical complications; nutritional support; cystectomy
• Additional Relevant MeSH Terms: Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Urinary Bladder Neoplasms
• Other Study ID Numbers: NL78792.031.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Patients are asked informed consent for data sharing with POLARIS consortium

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No