Late Side-effects After Cervical Cancer Treatment - Prevention and Treatment

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

• Symptoms of urinary incontinence [Срок оценки: From enrollment until the end of the treatment at 16 weeks]
• Symptoms and severity of anal incontinence [Срок оценки: From enrollment until the end of the treatment at 16 weeks]
• Symptoms of bowel dysfunction [Срок оценки: From enrollment until the end of the treatment at 16 weeks]
• Symptoms of sexual dysfunction [Срок оценки: From enrollment until the end of the treatment at 16 weeks]
• Pelvic pain symptoms [Срок оценки: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)]
• Symptoms of sexual distress [Срок оценки: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)]
• Quality of life questionnaire (EORTC QLQ-C30) [Срок оценки: From enrollment until the end of the treatment at 16 weeks]
• Quality of life QLQ-CX24 [Срок оценки: From enrollment until the end of the treatment at 16 weeks]
• Symptoms of secondary lower limb lymphedema [Срок оценки: From enrollment until the end of the treatment at 16 weeks]
• Pelvic floor muscle strength (digital palpation) [Срок оценки: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)]
• Pelvic floor muscle strength (pressure manometer) [Срок оценки: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)]
• Pelvic floor muscle resting tone [Срок оценки: From baseline clinical examination until endpoint clinical examination (after 16 weeks intervention)]