Clinical trial NCT06786091: Late Side-effects After Cervical Cancer Treatment - Prevention and Treatment
Official title: Late Side-effects After Cervical Cancer Treatment - Prevention and Treatment
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: NA
Conditions: Pelvic Floor Disorder
Female Pelvic Floor Dysfunction
Female Sexual Dysfunction
Female Urinary Incontinence
Fecal Incontinence
Secondary Lymphedema
Pelvic Pain
Keywords: feasibility studies
cervical cancer
pelvic floor muscle training
quality of life
pelvic floor morphology
pelvic floor muscle strength
Lead sponsor: St. Olavs Hospital
Sponsor class: OTHER
Collaborators: name: Sykehuset Ostfold
First posted: 2025-01-22
Enrollment: 40
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: Late side-effects following gynecological cancer are predominantly symptoms from the pelvic region originating from the bowels, urinary tract, lymphatic system, genitals and musculoskeletal system. Pelvic floor dysfunctions such as urinary- and anal incontinence, pelvic organ prolapse, vaginal stenosis as well as compromised sexual function and dyspareunia appear to be highly prevalent. The incidence of gynecological cancer in Norway was 1700 in 2020 and the survival rate in Norway is among the highest in the world. Most women with cervical cancers are treated with curative intension and life expectancy at 5 years after diagnosis is \>80%.

A negative impact of pelvic floor disorders on psychosocial well-being and quality of life are seen in survivors of gynecological cancer, and in cancer survivors this is found to be directly linked with patients regaining continence. Pelvic floor muscle training has few or no side effects, and is acknowledged as first line treatment for all types of urinary incontinence in women. Even though less studied, there is evidence to support pelvic floor muscle training as a safe intervention to reduce symptoms of anal incontinence and improve sexual function. A recent comparative cross-sectional study found that survivors of gynecological cancer with dyspareunia had higher stiffness and lower flexibility, coordination and endurance of the pelvic floor muscles compared to women with a history of total hysterectomy but no pelvic pain. These findings suggest a possible role for pelvic floor muscle training in the prevention and treatment of pelvic floor disorders after gynecological cancer. However, the overall quality of evidence for strengthening the pelvic floor muscles to reduce symptoms of pelvic floor dysfunctions after treatment of gynecological cancer is low.

This study aims to assess the feasibility of a digital pelvic floor rehabilitation programme led by an experienced pelvic floor physiotherapist. Study subjects are women treated for cervical cancer within the past 5 years, and all included participants will receive the intervention due to the feasibility design. Participants will be assessed clinically at baseline and endpoint, partly to ensure proper pelvic floor muscle contraction. The digital intervention ensures residents in rural areas equal access to specialized pelvic floor rehabilitation.

Detailed description: Introduction:

The primary goal of cancer treatment is to cure the disease or considerably prolong life, and secondary to improve the patient's quality of life. However, more than 500 distinct kinds of late side effects have been associated with modern cancer therapy ranging from minor, asymptomatic changes to life-threatening injuries and death. Many cancer survivors do not regain their previous level of health and functioning. Thus, as life expectancy after cancer is increasing, more people are living with substantial and permanent bodily changes negatively affecting quality of life. Based on this, the Norwegian Women's Public Health Association (N.K.S.) has identified a knowledge gap in cancer treatment, with a main focus on prevention and treatment on late side-effects in "cancer affecting women" in the strategic research plan for 2018-2024.

Gynecological cancer includes cancer in the cervix, uterus, ovaries/fallopian tubes and vulva with an estimated global prevalence of 1.31 million new cases each year. Women diagnosed with uterine-, ovarian/fallopian tube and vulvar cancer are on average aged \>60 years, while women diagnosed with cervical cancer are younger with a median age of 45 years. The incidence of gynecological cancer in Norway was 1700 in 2020b and the survival rate in Norway is among the highest in the world. Most women with cervical cancers are treated with curative intension and life expectancy at 5 years after diagnosis is \>80%.

Late side-effects following gynecological cancer are predominantly symptoms from the pelvic region originating from the bowels, urinary tract, lymphatic system, genitals and musculoskeletal system. Pelvic floor dysfunctions such as urinary- and anal incontinence, pelvic organ prolapse, vaginal stenosis as well as compromised sexual function and dyspareunia appear to be highly prevalent. According to a recent systematic review including 31 studies of pelvic floor disorders in gynecological cancer survivors, prevalence of urinary incontinence was reported up to 76%, fecal incontinence up to 37% and dyspareunia up to 58%. However, study quality tended to be poor, and the need for more comparative data on pelvic floor disorders among gynecological cancer survivors and the general population is highlighted by several studies included in the review. A negative impact of pelvic floor disorders on psychosocial well-being and quality of life are seen in survivors of gynecological cancer, and in cancer survivors this is found to be directly linked with patients regaining continence.

Pelvic floor muscle training has few or no side effects, and is acknowledged as first line treatment for all types of urinary incontinence in women, and mild-moderate pelvic organ prolapse. Even though less studied, there is evidence to support pelvic floor muscle training as a safe intervention to reduce symptoms of anal incontinence and improve sexual function. The pelvic floor muscles is a three-layered muscle group covering the inside of the pelvis constituting the "floor" of the truncus. This muscle group encloses the urethra, vagina and rectum, and is involved in the continence mechanism, elimination, sexual arousal and support of the pelvic organs. There is evidence that structured pelvic floor muscle training increases muscle volume and stiffness, closes the levator hiatus and elevates the resting position of bladder and rectum.

Gynecologic cancer therapy often includes multiple treatment modalities, all which alone and in combination have the potential to affect the pelvic organs and the musculoskeletal system. Nonetheless, it is likely that pelvic floor disorders following cancer treatment are associated, at least in part, with a deterioration in pelvic floor muscle function. The functional properties of the pelvic floor muscles following treatment of gynecological cancer is poorly studied. One small study found that both passive and contractile properties of the pelvic floor muscles was altered in women with urinary incontinence following surgery and radiotherapy of stage I and II endometrial cancer compared to women with urinary incontinence after benign hysterectomy. A recent comparative cross-sectional study found that survivors of gynecological cancer with dyspareunia had higher stiffness and lower flexibility, coordination and endurance of the pelvic floor muscles compared to women with a history of total hysterectomy but no pelvic pain. These findings suggest a possible role for pelvic floor muscle training in the prevention and treatment of pelvic floor disorders after gynecological cancer.

Nevertheless, the overall quality of evidence for strengthening the pelvic floor muscles to reduce symptoms of pelvic floor dysfunctions after treatment of gynecological cancer is low. Some studies suggest a positive outcome of pelvic floor muscle training on symptoms of urinary incontinence, however these results lack statistical power and must be interpreted with caution. There is evidence to suggest that pelvic floor muscle training improves sexual function and dyspareunia, whereas there is scarce documentation of pelvic floor muscle training as treatment for anal incontinence following gynecological cancer. There is no clear evidence that regular vaginal dilatation reduces or prevent the risk of vaginal stenosis after pelvic radiotherapy. However, observational studies suggest a positive association with lower rates of self-reported stenosis, and recommending regular vaginal dilation after radiotherapy is established practice. Low compliance rates have been noted, and lack of sufficient information are the most commonly reported barrier, resulting in uncertainty about dilator use. Recently, Cyr et al. (2020) shoved good feasibility and acceptability of multimodal pelvic floor physical therapy, including pelvic floor muscle training and use of a dilator, for gynecological cancer survivors with dyspareunia. The intervention also led to significant improvements in pain, sexual function, pelvic floor dysfunction symptoms and quality of life.

Over the past decade there has been increasing research and clinical interest in the role of exercise as an adjunct therapy to improve symptom control and management following cancer diagnosis. More recently the research field has been extended beyond symptom control to also include evaluation of benefits for cancer-specific outcomes, cancer progression and metastasis. Overall, general exercise is recommended for cancer survivors and there is evidence that exercise may improve cancer-related health outcomes such as anxiety, symptoms of depression, body image/self-esteem, sleep disturbance, fatigue, physical functioning and health-related quality of life. Despite this, adherence to the recommended physical activity and exercise guidelines among cancer patients appears to be poor. A recent systematic scoping review found that cancer patients believed that physical activity and exercise was beneficial for their physical health and well-being. However, lack of support and treatment related side effects acted as barriers. Group exercising with other cancer patients who face similar challenges was a major facilitator among most participants. The authors calls for innovative healthcare products and technologies designed to help manage cancer related side effects and enhance compliance to physical activity and exercise guidelines.

The adverse effects from the pelvic region may have a slow trajectory of onset and are thus more prone to being overlooked by clinicians after the initial stages of treatment is over. Radical surgical interventions result in immediate symptoms with the potential for improvement with time, whereas radiation tends to elicit late effects that manifest over many months. As such, pelvic floor dysfunctions and sexual morbidity remains a neglected aspect of routine follow-up for cancer, and the user organization highlights the need for increased focus on sexual health in cancer rehabilitation. The topic is still a taboo inhibiting both patient and health care professionals, resulting in patients suffering with symptoms for a long time without seeking help. Community-based studies have shown that embarrassment, lack of knowledge about the causes, unfamiliarity with treatment options and the presence of concomitant symptoms are reasons for not seeking medical treatment. A qualitative study among gynecological cancer survivors found that most women reported their pelvic floor dysfunctions to be a direct consequence of the cancer treatment. Despite severe symptom burden and negative impact on quality of life, most women found their own ways of coping with these symptoms. Lack of knowledge about existing treatment options was the most frequently reported reason for not seeking help. In the same study, 11 out of 15 informants stated that post-treatment care should be improved with regards to information, prevention and management of pelvic floor disorder.

To summarize, surgery, radiotherapy and chemotherapy alone or in combination may induce detrimental long-term side-effects in survivors of gynecological cancer. In parallel, advances in cancer treatment improve survival rates and in combination with an increasingly older population, more women are living with adverse effects of cancer and cancer treatment. These developments have transformed the experience of cancer from a potentially life threatening illness, to the current interpretation of cancer as a long-term or chronic condition. Unfortunately, there is less focus on how to prevent late side-effects, and even less on how to treat them. This project aims to improve the knowledge base on prevention and treatment of late side-effects following gynecological cancer. More specific, the project objective are to assess:

Feasibility of a web-based education and exercise rehabilitation intervention to reduce late side-effects following treatment of cervical cancer.

Novelty and ambition:

The project is a response to research needs identified by the N.K.S. on "cancer affecting women" and "sexual and reproductive health". Further the project concurs with the N.K.S. research strategy 2018-2024 to reduce health discrepancies through equal access to healthcare. The project is according to Stiftelsen Dam's area of attention "patient and user centered research" aiming to promote health and quality of life and prevent known late effects in gynecological cancer survivors.

The novelty of this study is improving the knowledge of interventions preventing and reducing late side-effects of cervical cancer. The financial burden of late side-effects of cancer is large for patients as well as society. The financial burden may be further increased in the future with increasing direct costs related to medical care, and treatment for long-term side-effects, as well as indirect costs related to factors such as loss of productivity in combination with higher survival rates. Health literacy entails a person's knowledge, motivation and competences to access, understand, appraise and apply health information. During the life course, health literacy is vital and enables a person to evaluate and make informed decisions concerning health care, disease prevention and health promotion in order to maintain or improve quality of life. The Government's strategy (2020-2023)c aims to strengthen the active patient role with regards to health and treatment, and to facilitate services specifically tailored to the individual patient's needs. The use of new technology and health services that can be adapted to a greater extent in the patient's own home is highlighted.

The innovation potential in the present proposal is related to improved clinical pathways with increased focus on prevention and treatment of pelvic floor disorders. The intervention has a holistic approach with information and practical guidance empowering women to take on responsibility for their condition with appropriate clinical assessment, support and treatment. Exercise is a well-recognized and cost-effective intervention for musculoskeletal diseases in the general population, and results from this project will be the starting point of a full scale randomized controlled trial. Patient-centred care improves disease outcomes and quality of life and health literacy is mandatory for patients to make informed decisions and actions for themselves. A digitally supervised early education and rehabilitation intervention to prevent or reduce bothersome late side-effects following gynecological cancer will ensure patients equal access to specialized health care and rehabilitation regardless of where they live. Moreover, a digital intervention does not require physical attendance and is considered less burdensome as the patients do not need to travel and can follow the exercise group from their own homes. The intervention also facilitates contact with other survivors of gynecological cancer as the digital meetings opens 30 minutes prior to exercise to allow participants to chat with each other or ask questions to the physiotherapist. As the health care services are becoming more digitalized, the present proposal may also provide firsthand experience with digital exercise groups which may be useful to other clinical fields.

Research questions and hypotheses, theoretical approach and methodology:

The overall aim is to investigate the feasibility of an early digital education and exercise rehabilitation program.

Hypothesis:

A four month, twice weekly web-based education and exercise intervention is feasible and will result in a reduction in late symptoms of pelvic floor disorders and sexual dysfunction following treatment of cervical cancer.

Methodology:

The study design is an observational two-centre study. Participants and settings: Patients diagnosed with cervical cancer at St. Olavs Hospital, Trondheim University Hospital and Østfold Hospital Trust within the last five years are eligible for this study. We aim to include up to 40 women. Eligible women will be identified through outpatient cervical cancer control lists. We therefore apply exemption from the confidentiality principle. The unique eleven digit ID number will be used to invite eligible women through Eforsk. The inclusion criteria are women aged 18 years or over diagnosed and treated for cervical cancer (radical surgery or radiotherapy) within the last five years, cancer stadium I-III and adequate knowledge in Norwegian. Exclusion criteria are age \>80 years, previous radiotherapy or pelvic surgery. Due to the design of a feasibility study, all included women will be offered the intervention. Study assessment visits: The clinical assessment visits are conducted with attendance at the outpatient clinic, Department of Physiotherapy. Baseline assessment will be done at study entry. Clinical assessment involves assessment of pelvic floor muscular strength and function. Strength and relaxation of the pelvic floor muscles are measured by a Camtech manometer. This involves the insertion of a small probe with a size smaller than a tampon into the vaginal opening. Further, strength and relaxation as well as muscular pain is assessed by internal palpation of the pelvic floor muscles in the vaginal opening. Some of the patients at St.Olavs hospital will be assessed by transperineal ultra sound imaging, involving an ultra sound probe at the perineum. The patients are reassessed after the 16-week intervention period. If the patient needs further individualized follow-up, contact will be established with a local primary health care physiotherapist. If relevant, patients will be referred to a gynecologist or sexual counselling.

Intervention:

The intervention consists of both exercise training, including pelvic floor muscle training, and information about the use of a dilator. At the baseline assessment participants are individually instructed in correct voluntary pelvic floor muscle contractions and how to perform intensive pelvic floor muscle training. The pelvic floor rehabilitation (pelvic floor muscle training and use of dilator) is supported with written information. The exercise program (aerobic and strength training, including pelvic floor muscle training) is provided with supervised digital group exercise sessions twice weekly and a home exercise program once weekly for 16 weeks. The home exercise program will be individualized if needed. The pelvic floor muscle training is following the recommendations for effective training dosage. The supervised digital exercise sessions are provided via www.join.nhn.no (Norsk Helsenett), and all sessions will open 30 minutes prior to exercise to allow for informal talk among participants and response to questions related to their treatment or training from the physiotherapist. Women will be offered individual video consultations for motivational talk in addition to the group sessions. Adherence to the exercise program is strongly emphasized and will be recorded in the patients' personal training diaries. Attendance in the digital group exercise will be registered by physiotherapists leading the group. Women not attending the group exercise sessions without prior notice will be contacted by telephone.

Outcome measures:

The primary outcome measures are to assess the willingness of participants to be included, their adherence and compliance to the intervention and response to the symptom questionnaires.

Secondary outcome measures are symptoms and severity of pelvic floor disorders, sexual function, lymphedema, quality of life and level of physical activity. Urinary incontinence are assessed using the International Consultation on Incontinence Questionnaire-UI Short Form (ICIQ-UI SF), an outcome measure developed to assess prevalence, severity, impact on quality of life and type of leakage. The short form has demonstrated satisfactory validity, reliability and sensitivity. Severity of anal incontinence symptoms is assessed with the widely used St.Marks incontinence score. The St. Marks score assesses frequency of stool and gas leakage, impact on daily life, urgency, pad use and use of constipating medication. Sexual dysfunction is assessed using the Amsterdam hyperactive pelvic floor scale (AHPFS) , the Female Sexual Distress Scale- revised (FSDS-R) and the Female Sexual Function Index. Quality of life is measured with The European Organization for Research and Treatment of Cancer Quality of Life core questionnaire (EORTC QLQ-C30) and QLQ-CX24. EORTC QLQ-C30 is a disease-specific instrument that is the instrument of choice in cancer trials in Europe. The EORTC QLQ-C30 incorporates nine multi-item scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and QOL scale. QLQ-CX24 is a cervical cancer-specific quality of life questionnaire module to be used in conjunction with QLQ-C30. Patient's impression of change is assessed by the Patient Global Impression of Change (PGIC). Secondary lymphedema will be assessed by the gynecologic cancer lymphedema questionnaire (GCLQ). Data regarding cancer diagnosis, treatment and potential medical events during the follow-up period will be collected from the patient medical records. Additionally, re-admission to hospital, ICD-10 diagnostic codes and in-hospital time will be recorded from the hospital records up to 12 months after completion of the chosen cancer treatment. In addition to the disease specific questionnaires, relevant baseline characteristics such as age, parity, type of delivery, menopause and vaginal supportive care, social status, education, frequency of physical activity, exercise activity and pelvic floor muscle training are collected on an digital questionnaire (eFORSK, https://www.klinforsk.no/info/Informasjon). Possible adverse events are recorded according to the CONSORT guidelines.

Statistics:

Statistical analysis include descriptive statistics, parametric tests for normal distributed data and non-parametric tests for skewed data

Sample size:

A power calculation is usually not advised when conduction a feasibility study, however, the sample size should be adequate to estimate critical parameters such as recruitment rate. Thus, it is suggested that recruiting 40 women may be sufficient.

User participation:

User involvement is ensured by including two members from patient interest organizations (Kreftforeningen and Gynkreftforeningen). The users are both survivors of gynecological cancer and trained in user involvement in research. So far, they have been consulted and provided valuable input on design of the intervention and follow-up. Further, they will be involved in the development and adaptation of the communication materials, and selection of questionnaires. The users are named as co-applicant for the funding and their time and travel expenses related to the project will be reimbursed. The phd-student will be the key person within the research team for users to contact. Further, N.K.S. research consultant Ida Heiaas and the N.K.S. "Womens health centre group" has contributed to the development of the study protocol.

Eligibility criteria: Inclusion Criteria:

* Women diagnosed and treated for cervical cancer (surgery, radiation- or chemo therapy) within the last five years
* Cancer stadium I-III
* Adequate knowledge in Norwegian.

Exclusion Criteria:

- Previous pelvic radiation therapy or pelvic surgery.

Primary outcomes:
measure: Feasibility - participants willingness to be included
timeFrame: The time frame is pre-defined as one year recruitment period
measure: Adherence - participants adherence to the intervention
timeFrame: From enrollment until the end of the treatment at 16 weeks
measure: Compliance to home exercises
timeFrame: From enrollment until the end of the treatment at 16 weeks
measure: Participants impression of change
timeFrame: From enrollment until the end of the treatment at 16 weeks
Secondary outcomes:
measure: Symptoms of urinary incontinence
timeFrame: From enrollment until the end of the treatment at 16 weeks
measure: Symptoms and severity of anal incontinence
timeFrame: From enrollment until the end of the treatment at 16 weeks
measure: Symptoms of bowel dysfunction
timeFrame: From enrollment until the end of the treatment at 16 weeks
measure: Symptoms of sexual dysfunction
timeFrame: From enrollment until the end of the treatment at 16 weeks
measure: Pelvic pain symptoms
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
measure: Symptoms of sexual distress
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
measure: Quality of life questionnaire (EORTC QLQ-C30)
timeFrame: From enrollment until the end of the treatment at 16 weeks
measure: Quality of life QLQ-CX24
timeFrame: From enrollment until the end of the treatment at 16 weeks
measure: Symptoms of secondary lower limb lymphedema
timeFrame: From enrollment until the end of the treatment at 16 weeks
measure: Pelvic floor muscle strength (digital palpation)
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
measure: Pelvic floor muscle strength (pressure manometer)
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
measure: Pelvic floor muscle resting tone
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
measure: Pain sensitization of the vestibulum
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
measure: Pelvic floor muscle morphology
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
measure: Physical activity (frequency)
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
measure: Physical activity (intensity)
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
measure: Physical activity (how long)
timeFrame: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)
Other outcomes:
Locations:
city: Trondheim
country: Norway
facility: St.Olavs University Hopsital
state: Trøndelag
city: Fredrikstad
country: Norway
facility: Østfold Hospital
state: Østfold
Study officials:
affiliation: St.Olavs university hospital
name: Signe Nilssen Stafne
role: STUDY_CHAIR
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