Trial Information

Efficacy of a Multimodal Rehabilitation Program to Bladder Cancer Patients

PhD protocol

Efficacy of Multi-professional Rehabilitation in Patients with Bladder Cancer (offered
radical cystectomy)

Bente Thoft Jensen, RN, MPH, research nurse Department of Urology Aarhus University
Hospital, Skejby

Supervisors:

Michael Borre, associate professor, DMSc, PhD, Department of Urology, Aarhus University
Hosptial, Skejby (head supervisor).

Klaus Ernst-Møller Jensen, consultant, DMSc, Department of Urology, Aarhus University
Hospital, Skejby

Sussie Laustsen, associate professor, PhD, Clinical Institut, Aarhus University

Mette Krintel Petersen, post-doc, PhD, research physiotherapist, Department of Physiotherapy
and Occupational Therapy, Aarhus University Hospital, Skejby

Collaborators:

Department of Physiotherapy and Occupational Therapy, Aarhus University Hospital, Skejby
Mette Borre, dietician, Department of Gastroenterology and Hepatology, Aarhus University
Hospital, Aarhus Sygehus, Norrebrogade Berit Kiesby, stoma-care nurse, Department of
Urology, Aarhus University Hospital, Skejby

Background In Denmark, the incidence of patients with bladder cancer is approximately 1800
cases annually; 75% of the cases are men. The disease is most frequent among the 50 to
80-year-olds and most cases are approximately 70 years old [1]. Recent studies have shown
that the incidence of bladder cancer is increasing in Europe[2]. Cystectomy is one of the
most comprehensive surgical procedures in urology[3,4]. In Denmark, the average
post-operative length of stay (LOS) was 19 days in 2005; the hospital mortality rate was
3.7% and 58% had a complicated course of disease. The mortality was comparable to
experiences abroad [3,5]. LOS is, however, long compared with high-volume hospitals with
well-defined clinical patient pathways [1,5,6]. Major surgery causes pain and stress-induced
catabolism leading to an unwanted metabolic and inflammatory response, impaired organ
function and risk of thrombosis. These conditions increase the risk of losing muscle mass
and reduce the activity level [2]. Overall, the above-mentioned circumstances delay the
rehabilitation process. The concept "fast-track surgery" is a multi-modal and
inter-professional approach to reduce post-surgical morbidity and optimise post-surgical
rehabilitation [7,8].

The multi-modal approach comprises both pre-operative optimisation of organ function,
patient education, effective pain management, early post-operative mobilisation and early
oral nutrition [9]. The concept has proven effective, though primarily documented in
connection with colorectal surgery [9-11,12,13,], with increased survival, reduced LOS and
reduced costs compared with conventional patient pathways[14,15]. The combination of a major
surgical intervention and an increasing number of elderly comorbid patients with bladder
cancer poses a challenge to treatment and care in all phases of the patient pathway. The
above studies primarily focus on the pre- and post-operative effort. Evidence is sparse
concerning the importance of an optimised pre-operative effort in rehabilitation [11]. It is
hypothesised that an optimised patient pathway calls for an inter-professional pre-operative
clinical evaluation and a pre-optimisation of the patient's general condition including
nutrition and physical activity[11,16-18]. There is low evidence of the efficacy of
multi-modal pre-optimisation efforts in major surgical procedures in urology [2,19].
Especially concerning the importance of a multi-facilitated pre-operative intervention for
rehabilitation and health-related quality of life [7,8]. Generally, there has been a
post-operative effect concerning early nutritional intervention and LOS [20]. Early
nutritional intervention increases the number of patients fulfilling the threshold for
sufficient nutritional status [15,21]. Nutrition strategies are increasingly combined with
physical training consisting of exercise to increase muscle strength and endurance, to
increase hypertrophy of muscle cells by increasing muscle protein synthesis and reducing
disintegration [22]. Thus, a pre-operative multi-modal intervention involving nutritional
optimisation and physical training should be a part of future studies. A muli-modal patient
pathway will involve expectations of an increased risk that the economic burden will shift
to the primary sector [23], an increased frequency of readmissions, complications and
reduced quality of life. This thesis investigates the efficacy of pre- and post-operative
multi-modal interventions in the rehabilitation of patients with bladder cancer undergoing
cystectomy.

Material: All patients undergoing cystectomy at Aarhus University Hospital in 2009
fulfilling the inclusion criteria.

Study A. To investigate the efficacy of pre- and post-operative multi-modal intervention in
bladder cancer patients referred to radical cystectomy

The following hypotheses are tested:

- An inter-professional multi-modal pre- and post-operative intervention promotes
rehabilitation and reduces length of stay

- The intervention group obtains a higher functional and activity level compared with the
control group

- The intervention group obtains a better management of urinary diversion compared with
the control group

Material and methods:

Primary endpoints: LOS is defined as number of post-operative days (until 7 defined
discharge criteria are fulfilled). The outcome data will be presented approximately 12
months after inclusion have been closed

Secondary endpoints:

- complications ( measured at discharge and 120 days postoperatively in average)

- Activity and functional level( will be measured every day during admission and 120 days
after discharge).Pfysical parametres like bioimpedance, musclepower and handgrip
strength will be measured at baseline( two weeks before operation, one day before
operation, at discharge and 120 days after operation in both arms)

- Patient-experienced quality during admission ( measured with EORTC-questionaire at
discharge in both arms)Informations will be presented approximately 12 months after
inclusion is closed

- Health-related quality of life will be measured at baseline and 120 days after
operation ( EORTC questionaire).

- Management of urinary diversion will be measured at baseline, before operation,35 days
and 120 days after operation.A validated stoma score scale for patient stoma skills
will be used.The outcome data will be presented approximately 12 months after inclusion
have been closed

Sample size. The study population is calculated on the basis on LOS for patients undergoing
cystectomy at the Department of Urology, Aarhus University Hospital, Skejby in 2008. Average
LOS was 13 days with a standard deviation of 4.75 days. Risk of type 1 error was 5% at a
2-sided analysis and strength at 80%. Lowest relevant difference in effect is a 20%
reduction in LOS in the intervention group. When a 2-sided comparison is made, 92 patients
have to be included; 46 in the intervention and control group, respectively.Written
information about the study is forwarded to the patients along with the appointment for a
uro-oncological evaluation.

Randomisation: Performed 14-17 days prior to surgery. When deciding on surgery the patient
receives oral information about the examination. After time for deliberation and giving
informed consent, the patients are randomised at the outpatient consultation following the
uro-oncological evaluation.

Monitoring:

Demographic and clinical background variables are registered at baseline. Follow-up after 4
months. Data are collected for further analysis at 1-year follow-up (appendix 1.1-1.5). All
patients undergo nutritional screening at baseline by NRS [32,33].

Patients with age-adjusted score<3 will receive supplements according to standard
criteria[25-28]. Energy demand is calculated as weight x100x1.3 KJ /day. Protein need is
calculated as weight x 1.5 gram protein/day. Fluid need is calculated as weight x 30 ml/day
[30]. Comorbidity is scored using the Charlson index score, pain and nausea using the
VAS-score [32,33].Habitual intestinal function is scored using the Bristol scale[34].

Physical activity level is estimated at baseline using the Physical Activity Scale (PAS)
[35]. Daily mobilisation time and walking distance are registered pre-operatively and during
admission using a pedometer [36,37].

Ability to perform personal activities of daily living are evaluated daily during admission
using the KATZ score [38].

Muscle power, muscle strength and body composition are registered at baseline,
pre-operatively, at discharge and 35, 120 (and 365) days post-operatively. Muscle power
(force x velocity) is evaluated by leg extensor power Rig [39]; Isometric muscle strength
(hand grip strength) is evaluated by "Good Muscle Strength" [40]and body composition is
evaluated by bioimpedance [41] Progression in management of urinary diversion is evaluated
by a categorial scale (appendix 1.4).

Standard treatment:

Patients eat normally until the operation. The rectal ampulla is emptied the evening before
surgery. From midnight the patients fast and drink two glasses of sweet juice at 06.00 am
before the operation. TED stockings are used to prevent thrombosis per- and post-operatively
until the mobilisation criteria have been met. 5000 IU of Fragmin are injected
subcutaneously from day 0. Individual prescriptions are made for patients with sclerotic
diseases. Per-operative infection prophylaxis is standardised.

Sevofluorane is used as a sedative and Bupivacain as well as Ultiva infusions as pain
management. Epidural catheter is used for pain treatment at th-12-L1 level. The transfusion
regime is standardised. Pain treatment: Post-operatively - epidurally administered
Bupivacain 2.5 mg /ml 5-6 ml / h in 3 full days. Peripheral pain treatment is tablet
paracetamol 1g x 4 and from day 2, two tablets Ibuprofen 400 mg x 3.

- Care of urinary diversion; When surgery is decided there is an interprofessional
meeting concerning management of stoma and neobladder. Stoma markings are made the day
before surgery in collaboration with the surgeon, the patient and the stoma care nurse.
Relevant aids are demonstrated and the post-operative regime is presented.

- Physiotherapy: Instruction and information about pulmonary physiotherapy is performed
pre-operatively. Daily mobilisation in each shift post-operatively.

- Discharge criteria (see appendix 1.5)

Intervention

In addition, the following initiatives are made in the intervention group:

- Pre-operative optimisation: The intervention group is taught pre-operatively about the
management of urinary diversion. Exercise kit is handed out with exercises to perform
in the home. Intensive instruction and teaching is provided by physiotherapist.
Moreover, plans for post-operative progressive mobilisation and transfer techniques.
Balancing mutual expectations for the entire intervention.

- Post-operative optimisation: Intensive, structured and progressive plans for daily
mobilisation and physical activity from the day of surgery until planned discharge at
7-9 post-operative day as well as instruction in urinary diversion by the stoma care
nurse.

Effect: Expressed as the difference in: LOS, complications, functional and activity level
and management of urinary diversion.

Statistics: Normally distributed data are described as mean, standard deviation (SD) and 95%
confidence intervals (CI) and tested with Student's t-test for paired data, unpaired data
are tested by unpaired t-test and repeated measurements. Non-normally distributed data are
described as median and range and tested by the Mann-Whitnew U-test or Wilcoxon's sign rank
test. When testing 3 or more variables the Friedman test is applied. Pearson's test is
applied in correlation analyses if conditions are met or Spearman's Rho. Frequencies are
compared by Fischer's exact test. Associations between variables are reported as odds ratios
and 95% CI.

Study B: Health-related quality of life and experienced patient quality in multi-modal
interventions

Purpose: to study the effect of multi-modal interventions concerning the patient experience
during hospital admission and health-related quality of life (HeQoL).

Hypothesis:

The intervention group will have better experienced quality and higher HeQoL. End points:
Score concerning HeQoL and patient experienced quality. Material /Method: Same method and
study population as in study 2. Disease-specific questionnaires from the European
Organisation for Research and Treatment of Cancer, EORTC QLQ-BLM30 and QLQ-C30 [42] were
applied. Scores are made at baseline and follow-up at planned control visits (35 days, 120
days and 365 days). At discharge EORTC In-PATSAT32 is used to evaluate the patient
experience of quality during admission. All questionnaires are validated and translated into
Danish [43,44].

Statistics study B. Data are registered at a categorial scale and described as mentioned in
study A for non-normally distributed data. Wilcoxon's sign rank test is used to test the
difference in HeQoL between the groups.When testing 3 or more groups, Friedman's test is
applied. Spearman's Rho is used for correlation analyses of non-normally distributed data.
Associations between variables are reported as ORs and 95% CI.

Ethical considerations: The study is approved by the Central Denmark Committee on Biomedical
and Research Ethics and the Danish Data Agency. Transport costs in connection with control
visits are refunded and it is attempted that examinations take place at days where the
patient has to meet for a control visit at the hospital. At present, the treatment offer to
this patient group does not include pre- and post-operative optimisation and it is not
deemed unethical to randomise patients to pre- or post-operative optimisation or standard
treatment, respectively. The study is registered in the American clinical database
www.clinicaltrials.gov.

Research plan including time schedule: Daily project management, data processing and
statistical analyses will be made and interpreted by PhD student Bente Thoft Jensen(BTJ),
who is also responsible for publication of results. Data collection will be made in
collaboration with the stoma care and nutrition responsible nurses and a dietician.
Instruction in home exercises, test of functional and activity level is made in
collaboration with the physiotherapists in the bladder team. The project is expected to
start in the spring 2011. Inclusion of patients will run for 1.5 years according to the
current surgical activity. Data collection and analyses are made in 2011 and 2012. Summary
and reporting of results will be made in 2012.

Publication: The project results are communicated in 3 peer-reviewed articles and in a PhD
thesis.

Funding:The project will be partly financed by the Department of Urology, Aarhus University
Hospital, Skejby (1/3), by the hospital management teat, Aarhus University Hospital, Skejby
(1/3) and the rest will be university scholar ships, industrial collaborators and
foundations.

Perspective: Cystectomy is one of the most resource-consuming surgical procedures. Despite
comprehensive shifts in paradigms in both nursing and treatment strategies throughout the
last decade, the average LOS has only been modestly reduced. In addition to the newly
introduced packages for diagnostics and treatment of cancer patients it is essential to
strengthen the overall effort. This PhD project should be seen as a part of the endavour to
fulfil all parts of the overall purpose concerning evidence-based optimisation of the
rehabilitation of bladder cancer patients. Whether urological patient pathways with a
pre-operative intervention can minimise post-operative complications, lead to a higher HeQoL
and shorten the rehabilitation period will be highlighted.