Earlier studies have shown that many patients (up to 30%) who have had a major surgery for rectal cancer, called a rectum amputation (where the entire rectum and anus are removed and the person gets a permanent stoma), still have trouble sitting and walking three years after the surgery. These problems are then seen as long-term or chronic.

WASA is a randomized multicenter international study that will test a way to reduce these problems. It will start in fall 2025 and go on for 3.5 years. About 300 patients will take part.

The patients will be randomly divided into two groups. One group will get guided online training twice a week, specially made for their needs. The other group will get information about the World Health Organization's (WHO) general advice on physical activity.

The idea is that special training during the first year after surgery will reduce problems with walking and sitting. If the hypothesis can be confirmed, it could lead to an easy and low-cost way to help many rectal cancer patients feel and function better.

Coordinating centre:

SSORG/Göteborg, Department of Surgery, Sahlgrenska University Hospital/Östra Principal Investigator: Charlotta Larsson MD, PhD Deputy Principal Investigator: Eva Haglind, MD, PhD, professor emerita Doctoral student: Lina Björklund Sand MD

Purpose and Aims:

The primary aim of the WASA trial is to evaluate the effectiveness of a structured physical activity program compared to standard WHO-based physical activity recommendations in reducing sitting and walking difficulties in patients who have undergone abdominoperineal excision (APE) for rectal cancer. The intervention secondary aims are to improve patient quality of life and reduce chronic pain and mobility issues post-surgery.

Background:

Surgery is the mainstay for curative treatment of the vast majority of rectal cancers, often in combination with chemoradiotherapy before the operation. For low rectal cancer abdominoperineal excision (APE) is performed, in cases with tumour involvement of the levators, including part/all of the levators in the removed specimen (ELAPE). In extralevator abdominoperineal excision (ELAPE) reconstruction of the pelvic floor is part of the procedure. All patients will have a permanent stoma.

In a national cohort of Swedish patients who had undergone APE/ELAPE during 2011 -2013 questionnaires distributed 3 years postoperatively and based on themes that occurred during semi-structured interviews before construction of the questionnaire, included questions about sitting and walking difficulties as well as pain. In the analyses we found that 20-25% of patients experienced sitting and/or walking difficulties, and/or pain, which thus should be regarded as chronic (1). In a multicentre, international and prospective study of patients with rectal cancer, we found that up to 30% of patients had sitting and/or walking difficulties 2 years after APE and that significantly fewer patients who had been operated by an anterior resection experienced such problems (2).

Few if any other reports have focused on these problems, which could lead to impairments of normal daily living.

The aim of this trial is to compare the effect an intervention consisting of a specific program of physical activity introduced before surgery and continued for 12 months after surgery in comparison with a control group receiving information about physical activity as recommended by WHO.

The underlaying hypothesis is that by increasing muscle mass and -strength in muscle groups in the pelvis, lower abdominal and upper thigh area as well as balance training the difficulties in sitting and walking after abdominoperineal excision will decrease.

Study plan, preliminary results and clinical relevance

Study design

The design is randomized, international, multicentre comparing an intervention consisting of a specific, supervised live online training program introduced after diagnosis and before surgery/neoadjuvant treatment with adaptions immediately after surgery (index surgery) with a control group where patients are carefully informed of the physical activity as recommended by WHO. The design involves all consecutive, consenting patients with rectal cancer to be treated by APE with/without neoadjuvant treatment in participating hospitals.

The randomization will be stratified by ELAPE/APE, hospital and neoadjuvant treatment.

Patients will be accrued from the hospitals within the SSORG network and consenting to participate in the trial after information. Other surgical departments with interest are welcome to join in the trial. Patients will undergo surgery, follow-up and adjuvant treatment according to local routine.

Training program

Intervention group After inclusion and consent the patients are instructed trough an online leader-led group training program consisting of specific training of mainly levator, abdominal, quadriceps (all portions) and gluteal muscles as well as endurance training. They are given information about WHO recommendation about physical activity. The patients are asked to sign up for two specific training sessions per week. Group size maximum 10 patients.

Control group After inclusion careful instruction about WHO recommendations on physical activity with 30 min aerobic physical activity 5 times per week/150 min per week plus strength sessions twice weekly.

Outcome Measures

• Primary Outcome: Measurement of self-reported sitting and walking difficulties at 12 months post-surgery.
• Secondary Outcomes: Measurement of self-reported sitting and walking difficulties at 6 and 24 months post-surgery, objective measures including a 6-minute walking test and standardized balance tests, complications, patient-reported outcomes on pain, bodily functions, quality of life, cognitive function, and level of physical activity, along blood and faecal analyses, radiological changes and health economic analyses.

Statistical Considerations and Sample Size Calculation

The study is planned with an adaptive design, with an interim analysis after 50 participants. A team comprising a statistician and two scientists, including at least one clinician experienced in RCTs, will assess the primary outcome at six months. The analysis will be blinded to group identities and will determine the intervention's effect size. The results will guide on whether to adjust the sample size or intervention, especially if effects are smaller than expected.

Lacking prior data on this new physical activity intervention, we set an initial sample size aiming for a 50% improvement in severe sitting and walking difficulties in the intervention group compared to controls. Based on prior findings showing 30% prevalence of such issues and calculated with 80% power and a significance level of p<0.05, the required sample size was 121 patients per group. To account for non-compliance, 29 additional patients per group were added, resulting in a total of 300 participants, split evenly between the two groups.

Data Collection

Objective data to assess physical strength etc will be collected at baseline, at 6 and 12 months postoperatively. Patient reported data will be collected using a combination of online and paper-based methods. Baseline data will be collected at diagnosis with follow-up questionnaires administered at 6, 12, and 24 months post-surgery. These will cover aspects from socio-economic status to pain, quality of life, and kinesophobia. The tools will include established instruments like KASAM and custom scales derived through clinimetric methods (face-validated). Clinical data will be collected through national registers.

Data Analyses and Statistical Methods

Primary analyses will employ intention-to-treat approach, corrected for stratification variables and potential confounders. Descriptive statistics will summarize baseline characteristics, with inferential statistics (e.g., chi-squared tests, ANOVA) applied to primary and secondary outcomes. Multivariate regression analyses will explore predictors of successful outcomes, and health economic evaluations will assess cost-effectiveness.

External validity All patients with rectal cancer to be treated by abdominoperineal excision will be registered in the "screening log", including patients who do not meet the inclusion criteria, patients excluded after randomization, patients not giving consent to participation as well as those missed. All should be registered concerning date of diagnosis, sex, age, ASA class, cTNM, neoadjuvant treatment yes/no, type of operation/s. The reason for non-inclusion or exclusion will be noted.

Registration The trial is registered at ClinicalTrials.gov (No. [XXXX]) ensuring transparency and adherence to international standards.

Ethical Approval Ethical approval has been secured in Sweden (Swedish Ethical Board Authority approval No. 2024-08611-01) Informed consent will be obtained, respecting participant autonomy and confidentiality. The trial will be conducted according to the Helsinki declaration.

Timeline

1. Months 0-6: Finalize protocol, obtain ethical approval, and begin recruiting participants.
2. Months 7-18: Continue recruitment, involve more centers, initiate intervention, and collect baseline data and begin follow-up data collection.
3. Months 19-36: Complete intervention, conduct interim analyses, and begin follow-up data collection.
4. Months 37-48: Data collection outcome at 6 months, comprehensive data analysis, and dissemination of results. Follow up data collection.
5. Months 49-72: Data collection for outcome at 12 and 24 months, comprehensive data analysis, and dissemination of results

Clinical Relevance

The trial is clinically significant as it addresses the unmet need for effective postoperative rehabilitation in rectal cancer patients undergoing abdominoperineal excision (APE). This surgery, while necessary, leads to chronic mobility issues, such as sitting and walking difficulties, in up to 30% of patients, affecting their quality of life as well as activities of daily life. Standard postoperative care, which follows general physical activity guidelines, may not sufficiently address these challenges.

The trial evaluates a targeted exercise program designed to enhance muscle strength and balance. By doing so, it aims to directly address the mobility issues faced by patients post- surgery. If our hypothesis is correct, implementation of more effective rehabilitation strategies, improving functional outcomes and overall patient well-being should follow.

Additionally, by integrating health economic analyses we assess the cost-effectiveness of the intervention.

Preliminary Results

Unpublished (accepted in Diseases of the Colon and Rectum) data from our previous study comparing difficulties sitting and walking after APE versus anterior resection shows that this is much more frequent after APE and we therefore only include theese patients in the WASA-study.

Feasibility and Infrastructure

Feasibility The trial is coordinated by the Scandinavian Surgical Outcomes Research Group SSORG.The steering committee consists of experienced researchers with extensive knowledge in clinical RCT studies. There is a well established structure for managing recruitment and data. Data retrieval, management and analyses will be conducted using secure platforms (e.g., REDCap), ensuring high data integrity and participant privacy. Collaboration with other participating hospitals is established.

Infrastructure The Scandinavian Surgical Outcomes Research Group SSORG - established in 2009 at Sahlgrenska University Hospital is led by Professor Eva Haglind together with Professor Eva Angenete, who with associate professor Jennifer Park, me and two other post-docs constitute the senior researchers. Five PhD students are part of the group. Moreover there are three research nurses, a study administrator, one data manager (50 %) and two statisticians (80%). Collaborations frequently occur with other hospitals and regions, and the close cooperation with two university hospitals in Denmark have been ongoing since SSORg was established.

Inclusion Criteria:

• Patients with rectal cancer to be treated with/without neoadjuvant (chemo)radiation and abdominoperineal excision with or without mesh (APE/ELAPE) Informed consent Able to read and understand Swedish or Danish

Exclusion Criteria:

• Patients with rectal cancer to be operated by extended abdominoperineal excision (ELAPE) requiring musculocutaneous or muscular flaps to be operated by Hartmann's procedure to be operated by anterior resection (low or high) participation in other randomized trials in conflict with the protocol and endpoints of the WASA trial Not understanding Swedish or Danish Patients reporting habit of physical activity exceeding the WHO-recommendations (150 min + two strength sessions) at baseline.