ERAS for Ambulatory TURBT: Enhancing Bladder Cancer Care (EMBRACE) randomised controlled trial protocol

Current state of knowledge

Bladder cancer is the 10th most common malignancy diagnosed in the world, with approximately 600 000 new cases and 200 000 deaths attributed to the disease in 2020.1 Non-muscle invasive bladder cancer (NMIBC) accounts for 75%–80% of cases and is associated with a 5-year cancer-specific survival ranging from 71% to 96% depending on tumour characteristics.2 3 Despite favourable survival, high rates of disease recurrence and progression necessitates the need for intense treatment and surveillance in these patients.4

Unfortunately, the physical, psychological, social and financial burdens of living with bladder cancer can be enormous for patients and families.5 6 Health-related quality of life (HRQoL) significantly declines after diagnosis and to a greater extent compared with other pelvic malignancies.7–9 As a result, there has been a growing awareness of the need to embrace a model of survivorship in bladder cancer that (1) minimises treatment and surveillance-related morbidity and (2) improves HRQoL.10 11 One aspect of NMIBC management that can be optimised is the care pathway surrounding transurethral resection of bladder tumours (TURBT), the endoscopic procedure used to diagnose and treat initial and recurrent bladder tumours.

TURBT is one of the more common operations performed by urologists with approximately 100 000 procedures performed in the ambulatory setting in the USA in 2020.12 TURBT is often described to patients as a ‘well-tolerated’ and ‘incision-free’ procedure to diagnose and treat NMIBC. However, for many patients, this depiction is not an adequate representation of the degree of anxiety, pain and lower urinary tract dysfunction that can be experienced with the procedure.13–15 Thus, significant opportunity exists to reduce the degree of distress and discomfort associated with ambulatory TURBT, especially given that (1) the majority of challenges patients experience occur after they are discharged home and (2) the proportion of TURBTs being performed in the ambulatory setting (vs hospital setting) is increasing globally.16–18

Redesigning care pathways to improve outcomes is an essential component of delivering high-quality, patient-centred care and embracing a model of survivorship in bladder cancer. One such way of redesigning care pathways is through an enhanced recovery after surgery (ERAS) protocol. ERAS refers to a pathway designed to optimise experience of care and recovery as patients progress through the different phases of surgery (ie, preoperative, intraoperative and postoperative phases). ERAS protocols have proven to be highly successful in reducing complications, shortening length of stay and improving HRQoL across a variety of different major surgical procedures, including radical cystectomy and prostatectomy.19 20 More recently, ERAS protocols have been adapted to the ambulatory setting with early evidence demonstrating similar benefits to patients, particularly related to postoperative pain control and reducing unplanned visits to the emergency department (ED).21–23 Unplanned ED and clinic visits due to pain, haematuria and Foley catheter issues are not uncommon after TURBT and have been identified as areas in need of improvement.24 25

An ERAS protocol to enhance the care pathway of ambulatory TURBT has yet to be proposed or evaluated. Such a protocol could have a profound impact on alleviating distress and discomfort in patients who have an impending bladder cancer diagnosis and require a TURBT. Most importantly, from the perspective of survivorship in bladder cancer, an ERAS protocol has the potential to improve the experience of care in a population of patients who often require multiple TURBTs over their lifetime due to recurrent tumours.

The ERAS for Ambulatory TURBT: Enhancing Bladder Cancer Care (EMBRACE) Trial is a single-centre, randomised controlled trial evaluating the impact of a novel ERAS protocol for ambulatory TURBT in patients with bladder cancer. We hypothesise that patients exposed to the ERAS protocol will experience a higher quality of recovery after ambulatory TURBT compared with those receiving usual care.

Study objectives

The main objective of the trial is to determine whether an ERAS protocol improves the quality of recovery after ambulatory TURBT. The primary study endpoint is the mean change in Quality of Recovery 15 score (QoR-15) score in the ERAS and usual care groups as measured over the day of surgery (DOS) and postoperative day (POD) 1. We hypothesise that QoR-15 scores over the DOS and POD1 will be significantly higher in the ERAS group compared with the usual care group.

The secondary objectives are to evaluate the impact of the ERAS protocol on pain, lower urinary tract symptoms, haematuria, satisfaction, anxiety, morphine milligram equivalents (MMEs), ED visits, clinic visits, phone calls and electronic message utilisation. The rate of complications and unplanned admissions from the postanaesthesia care unit will also be assessed.

Study design and setting

EMBRACE is a single-centre, randomised controlled trial to investigate the effectiveness of an ERAS protocol compared with usual care in patients with bladder cancer undergoing ambulatory TURBT (figure 1). The trial is being conducted within two ambulatory surgery units at Johns Hopkins Hospital (JHH) in Baltimore, MD as of Summer 2023. This protocol adheres to Standard Protocol Items: Recommendations for Interventional Trials guidelines.

Figure 1

Flow chart. DOS, day of surgery; ERAS, enhanced recovery after surgery; MIBC, muscle invasive bladder cancer; MME, morphine milligram equivalent; POD, postoperative day; UTI-SIQ-8, Urinary Tract Infection-Symptom and Impairment Questionnaire; VAS, Visual Analogue Scale.

Participant eligibility, consent and randomisation

Patients with suspected or known bladder cancer aged ≥18 years undergoing initial or repeat TURBT are approached for potential study enrolment. Patients must have a procedure planned for the ambulatory setting with anticipated discharge home on the same DOS. Consent is obtained in clinic or over the telephone by study personnel at least 5 days prior to a scheduled TURBT. A copy of the study consent form can be found in online supplemental materials. Recruitment is carried out from urology outpatient clinics or operating room schedules from any of four urological oncologists performing ambulatory TURBTs at JHH. Patient exclusion criteria are as follows: (1) undergoing a planned concomitant procedure (eg, ureteroscopy), (2) unable to consent for themselves, (3) unable to complete telephone-based follow-up after discharge home and (4) undergoing TURBT for the treatment of muscle-invasive bladder cancer (ie, trimodal therapy). Once consented, patients will be randomised between the ERAS and usual car arms. A stratified randomisation scheme will be used, with blocking within strata. Stratification factors include patient sex and whether they have undergone a TURBT previously or not to prevent key imbalances between the ERAS and usual care groups.26 Equal allocation by strata will be used so that differences among patient categories will be balanced. The Moses-Oakford algorithm will be used to generate the random assignments with equal allocation within blocks.27 An independent statistician will oversee the allocation sequence and randomisation. Participants and study personnel will not be blinded for this trial.

Primary outcome

The primary study endpoint is the mean change in QoR-15 score between DOS and POD1, which will be compared between the ERAS vs usual care groups. The QoR-15 score is a validated 15-item questionnaire that assesses quality of recovery in five dimensions: pain, physical comfort, functional autonomy, emotions and psychological support.28 29 Each item is scored 0–10 with higher scores representing superior quality of recovery (the score is a continuous variable ranging from 0 (worst) to 150 (best quality of recovery)).28 29 The QoR-15 score is patient-reported outcome measure and has been extensively used to evaluate ERAS for both inpatient and ambulatory surgeries.30–32 It is a shorter and more patient-friendly version of the QoR-40 with equivalent psychometric properties.33 We chose to examine mean change in QoR-15 between DOS and POD1 between the two study groups to account for (1) the fact that recovery starts prior to surgery with adequate patient education and support and (2) the first day after surgery is the worst for patients in terms of physical and mental well-being based on our needs assessment.

Secondary outcomes

A Visual Analogue Score (0–10) will be used to measure the severity of dysuria, suprapubic/bladder, urethral, penile and vulvar pain. The Urinary Tract Infection-Symptom and Impairment Questionnaire, a validated questionnaire of voiding symptom severity and bother, will be used to measure lower urinary tract dysfunction.34 Satisfaction with the TURBT care pathway will be measured on a self-reported scale of 0–10. Patients will be queried about their degree of haematuria (none, pink, red, red with clots) and incontinence (pads per day). The medical record will be used to estimate the MME and the number of outpatient visits, ED visits, hospital readmissions, patient phone calls and electronic messages that occur in the first 30 days after surgery. The rate of complications by Clavien-Dindo classification and unplanned admissions from the postanaesthesia care unit will also be assessed.35

Sample size

We hypothesise that the ERAS protocol will improve the mean change in QoR-15 score between DOS and POD1 by a minimum of 6 points compared with usual care, which would reflect a clinically important difference in quality of recovery.36 We assumed an SD=12 based on prior literature,30 compound symmetry covariance structure and two-sided alpha=0.05. With 50 patients per group (n=100), the study has 87% and 82% power to detect a minimum 6-point difference in the mean change in QoR-15 between ERAS vs usual care,36 conservatively assuming a correlation between the DOS and POD1 scores of 0.3 and 0.5, respectively.37 Of note, under the less conservative assumption that the ERAS protocol is unlikely to be worse than usual care, a one-sided test would achieve 93% and 89% power. Power was calculated with PASS 2021 (NCSS Software, Kaysville, Utah, USA).

Follow-up and data collection

Primary and secondary outcomes will be assessed at four time points: at enrolment (in-person or via telephone) and on the DOS, POD1 and POD2 (via telephone). Although study outcomes are assessed at the points listed above, a window of 48 hours (eg, POD2±2 days) is allowed for each assessment to account for rare cases when patients cannot be reached. Patient, procedural and pathology characteristics will be abstracted from the electronic medical record throughout the study and on POD30 to identify any procedure-related complications or readmissions (table 2). All data will be housed in an electronic repository prior to analysis.

Statistical analyses

Patients randomised to ERAS and usual care will be compared with respect to age, sex, race, TURBT history, tumour stage and grade to determine how well the randomisation achieved balance. Continuous and categorical variables will be compared using the Wilcoxon rank sum test and χ² test, respectively. Repeated measures analysis of variance or covariance (RMANCOVA) will be used to compare ERAS versus usual care patients with respect to the mean change in QoR-15 score between DOS and POD1. Any potential between-subject confounding factors not balanced by the randomisation will be included as factors in the RMANCOVA. Potential confounders may include a history of diabetes, body mass index, use of intravesical chemotherapy and whether a patient is discharged home with a Foley catheter or not. Analyses will be performed using SAS V.9.4 (SAS Institute).

Safety reporting

Minimal risk is assumed for the study. However, adverse events and unanticipated problems involving risks to subjects or others are reported the JHH IRB in writing within 24 hours of the event occurring. All information is collected on study-specific case report forms by study staff. Scheduled meetings take place quarterly and include the principal investigator and all research staff involved with the conduct of the protocol. During these meetings, matters related to the following are discussed: safety participants, validity and integrity of the data, enrolment rate relative to expectation, characteristics of participants, adherence to protocol (potential or real protocol violations), data completeness and progress of data for objectives.

Patient

Prioritising patients’ perspectives in the development of an ERAS protocol is critical to its success.38 39 To ensure a patient-centric design our protocol, patient input was obtained in two ways: (1) from feedback obtained from a convened panel of patients with bladder cancer who have undergone TURBT at JHH or elsewhere and (2) from 150 patients enrolled in a previously conducted prospective cohort study evaluating symptoms and experience of care after ambulatory TURBT at JHH.17 Patient feedback was used to generate educational materials about preparing to undergo TURBT and our patient panel critically reviewed and edited these documents prior to finalisation. Patients will not be involved in study recruitment. The results of the EMBRACE trial will be shared with our panel of patients with bladder cancer. Of note, the burden of the trial was assessed by our patient panel and was felt to be reasonable.