Lymphedema After Gyneco-oncologic Treatment

Study Overview
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Brief Summary
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Trial developed to inventory the incidence of early and advanced stage lower limb lymphedema in patients diagnosed with and treated for gynaecologic cancer. Four hundred patients with diagnosis stage 1-3 gynaecologic cancer will be included in an observational cohort at the moment of diagnosis and followed for occurrence of lower limb lymphedema up till 2 years after their last treatment. Data on signs and symptoms, quality of life, time investment and financial expenses will be collected, to provide information on the incidence and risk factors for lower limb lymphedema, and on its impact on patients, regarding quality of life, sexual well-being and time- and financial investment. Patients developing early stage LLL enter an interventional sub-cohort, in which the effect of class II compressive garments on preventing evolution towards advanced stage LLL will be evaluated.

Detailed Description
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Context of the problem: Improved knowledge on the diagnosis and treatment of cancer has resulted in an increased number of cancer survivors. Consequently, more patients are confronted, often life-long, with the complications of their cancer treatment. These chronic conditions impact daily functioning and quality of life (QoL), complicate the return to work and undermine psycho-social well-being. One of the most frequent and disabling complications is lymphedema, a condition undermining QoL to an extent exceeding even a 10-year age increase. The damage of lymphedema covers many aspects of daily life: it changes body image and complicates daily activities as basic as clothing, it increases patient-related health expenditures for treatment and for coping with the disease, reduces patient autonomy in daily functioning and can even cause sensory or motor dysfunctions. So far, no definitive cure exists for lymphedema: patients are confined to life-long preventive measures, compression therapy and regular manual lymph drainage. Surgical repair may be an option in selected cases, but evidence on surgical techniques is limited and their long-term effects are still unknown. Moreover, even after successful repair, conservative treatment is still needed. Most studies on lymphedema are limited to upper limb lymphedema (ULL), mainly after breast cancer treatment. Only a few publications focus on lower limb lymphedema (LLL), despite its detrimental impact on QoL. This could be due to the difficulties to diagnose and treat LLL in comparison to ULL: LLL often occurs bilaterally or at the level of the groins or genital region, hence impeding diagnosis through comparison. Perimetric measurement of large cone-like oedematous legs is cumbersome. Manual lymph drainage and application of compressive garments is more strenuous for legs than for arms, and the typical bilateral occurrence and large volumes of LLL inflate the cost of treatment garments. However limited, some groups did evaluate the incidence of LLL after pelvic treatment, but maintained the criteria for advanced stage lymphedema as cut off, thereby underestimating the prior phases in which patients are confronted with functional impairment due to LLL, without apparent swelling. The observational cohort in this study is aimed at inventorying the incidence, timing and risk factors of early as well as advanced stage lymphedema. Time and cost-investment of patients for prevention and/or treatment of LLL will be analyzed. The impact of LLL on QoL and on sexual well-being will be calculated. A sub-cohort of this trial is of interventional design: in patients, included in the observational cohort and developing early stage LLL, standard of care treatment will be started, including skin care, active exercises and manual lymph drainage. In the experimental group, compressive garments class II will be added and compliance as well as tolerance of these garments will be analyzed. Side-kicks of this trial are the standardization of perimetric measurements of the legs, validation of a self-report LLL screening tool and testing of the sensitivity and specificity of ICG fluoroscopy to detect early stage LLL.

Official Title
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Lower Limb Lymphedema After Gyneco-oncologic Therapy: Can we Prevent Irreversible Lymphedema?

Conditions
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Lymphedema, Genital Neoplasm

Intervention / Treatment
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* Device: Compressive garments class II


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent (ICF) Female patient, recently diagnosed with gynaecologic cancer (cervix, endometrium, vulva, vagina, ovaries…) and candidate for curative treatment Age ≥ 18 years Understanding of the Dutch language Able to understand the informed consent and willing to comply with the protocol, including use of diary or app and timely completion of requested questionnaires. Exclusion Criteria: History of treatment for gynaecologic cancer Concurrent second primary tumor(s) Pregnancy or pregnancy planned within 2 years Known metastasized cancer at the time of inclusion (D0) Severe injury, surgery or deformation of the legs or groins in the past Vascular malformation of the leg or untreated venous insufficiency with oedema (CEAP C4 or more) Mental or psychological problems, inability to comply to the study protocol First treatment already started

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Observational cohort<br>Patients diagnosed with curable gynaecologic cancer and accepting to participate before start of any gyneco-oncologic treatment. | |
| Interventional subgroup<br>Patients in the observational cohort, who develop early stage lymphedema (ISL stage 0-1): they will enter a randomized non-blinded interventional subgroup, comparing standard of care preventive measures only or in combination with compressive garments (compression class II) | Device: Compressive garments class II<br>* Daily wearing of compressive garments, especially during prolonged standing upright or strenuous activities.<br>* Other names: Flat knit Medi Cosy compression class II stockings and/or bermuda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence rate of LLL | Number of patients with transition (evolution) to stage 0-3 LLL (ISL criteria) in the first two years after treatment for gynecologic cancer. We defined three potential transitions: T1: from no LLL to reversible stage 0-1 LLL T2: from no LLL to irreversible stage 2-3 LLL T3: from stage 0-1 LLL to stage 2-3 LLL | From diagnosis until 2 years after last oncologic treatment | 
| Incidence rate of transition from stage 0-1 LLL to stage 2-3 LLL in randomized subgroup | Number of patients diagnosed with stage 0-1 LLL within one year after treatment for gynecologic cancer and that evolve from stage 0-1 LLL to stage 2-3 LLL | From transition to stage 0-1 LLL until 1 year after | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Timing of development of LLL | Registration of the timing of development of the different stages of LLL within the first two years after end of treatment | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - per age category the number of patients that develop lower limb lymph-edema as assessed with ISL criteria | Age: the amount of time something has been alive or has existed (years) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - weight | Weight: In the operational definition, the weight of an object is the force measured by the operation of weighing it, which is the force it exerts on its support, expressed in kilograms (kg) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - height | Height: measure of vertical extent (how tall something or someone is) (expressed in meters) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - per BMI category the number of patients that develop lower limb lymph-edema as assessed with ISL criteria (reported value) | Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and height in metres. | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - per category of physical activity the number of patients that develop lower limb lymph-edema as assessed with ISL criteria | Physical activity is defined as any voluntary bodily movement produced by skeletal muscles that requires energy expenditure. Physical activity encompasses all activities, at any intensity, performed during any time of day or night. It includes both exercise and incidental activity integrated into daily routine. This integrated activity may not be planned, structured, repetitive or purposeful for the improvement of fitness, and may include activities such as walking to the local shop, cleaning, working, active transport etc. Expressed in intensity level (categorical) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - Marital status | Civil status, or marital status, are the distinct options that describe a person's relationship with a significant other. Married, single, divorced, and widowed are examples of civil status. Expressed in definition (categorical - married, divorced, widowed, single...) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - obstetrical status | Obstetrical history: medical specialty dealing with the care of all women's reproductive tracts and their children during pregnancy (prenatal period), childbirth and the postnatal period Obstetric state: gravida - partus - abortus - mater | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - education status | The International Standard Classification of Education (ISCED 2011) is a statistical framework for organizing information on education maintained by the United Nations Educational, Scientific and Cultural Organization (UNESCO). It is a member of the international family of economic and social classifications of the United Nations. Categorical: lower secondary education, upper secondary education, Bachelor's or equivalent, Master's or equivalent, Doctorate or equivalent... | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - employment status | Work or labor (or labour in British English) is intentional activity people perform to support themselves, others, or the needs and wants of a wider community Categorical: unemployed, employee, self-employed, retired, student, work-incapacity... | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - smoking status | Smoking is a practice in which a substance is burned and the resulting smoke is typically breathed in to be tasted and absorbed into the bloodstream. Expressed in categories (never, used to smoke, active smoker) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - pack-years | Smoking is a practice in which a substance is burned and the resulting smoke is typically breathed in to be tasted and absorbed into the bloodstream. A pack-year is a clinical quantification of cigarette smoking used to measure a person's exposure to tobacco. This is used to assess their risk of developing lung cancer or other pathologies related to tobacco use. Calculation: Number of pack-years = (number of cigarettes smoked per day/20) × number of years smoked. (1 pack has 20 cigarettes in some countries) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - alcohol intake | An alcoholic drink (also called an alcoholic beverage, adult beverage, or simply a drink) is a drink that contains ethanol, a type of alcohol produced by fermentation of grains, fruits, or other sources of sugar that acts as a drug. Expressed in categories: never, occasionally, daily | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - physical appearance | Human physical appearance is the outward phenotype or look of human beings. Registered as importance adhered to physical appearance on a rating scale from 1 to 10. Expressed on a scale of one to ten, (this scale is a general and largely vernacular concept used for rating things, people, places, ideas, and so on. The scale has 10 as a maximum score, as a denotation of exceptionally high quality or of another attribute, a minimum of 0.) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - household income category | Household income is an economic standard that can be applied to one household, or aggregated across a large group such as a county, city, or the whole country. It is commonly used by government and private institutions to describe a household's economic status or to track economic trends. Expressed in categories (per month): <1500, 1500-3000, >3000-5000, >5000 or 'does not wish to respond' | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - number of patients with contact allergy that develop lower limb lymph-edema as assessed with ISL criteria | Allergies, also known as allergic diseases, are a number of conditions caused by hypersensitivity of the immune system to typically harmless substances in the environment. | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - number of patients with medical record of disease (renal, cardiac, diabetic...) that develop lower limb lymph-edema as assessed with ISL criteria | The medical history, case history, or anamnesis of a patient is information gained by a physician by asking specific questions, with the aim of obtaining information useful in formulating a diagnosis and providing medical care to the patient. Expressed in relevant categories (cardiac, renal, vascular, cancer, auto-immune...) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - pain score | A pain scale measures a patient's pain intensity or other features. Pain scales are a common communication tool in medical contexts, and are used in a variety of medical settings. Expressed on a scale of one to ten, (this scale is a general and largely vernacular concept used for rating things, people, places, ideas, and so on. The scale has 10 as a denotation of exceptionally high pain, and a minimum of 0 for no pain at all.) | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - tumor stage (TNM) | The TNM Classification of Malignant Tumors (TNM) is a globally recognised standard for classifying the extent of spread of cancer. It is a classification system of the anatomical extent of tumor cancers. Most common tumors have their own TNM classification. Sometimes also described as the AJCC system. TNM is a notation system that describes the stage of a cancer, which originates from a solid tumor, using alphanumeric codes: T describes the size of the original (primary) tumor and whether it has invaded nearby tissue, N describes nearby (regional) lymph nodes that are involved, M describes distant metastasis (spread of cancer from one part of the body to another). | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - tumor stage (FIGO) | The International Federation of Gynaecology and Obstetrics, usually just FIGO as the acronym of its French name Fédération Internationale de Gynécologie et d'Obstétrique, is a worldwide non-governmental organisation representing obstetricians and gynaecologists in over one hundred territories. The FIGO staging system is used most often for cancers of the female reproductive organs, including cervical cancer, endometrial cancer, ovarian cancer... As a rule, the lower the number, the less the cancer has spread. A higher number, such as stage IV, means a more advanced cancer. And within a stage, an earlier letter means a lower stage. Cancers with similar stages tend to have a similar outlook and are often treated in much the same way. | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - the number of patients with limited (only one or two gynaecologic organs) or extensive surgery (multiple organs and/or lymph nodes) that develop lower limb lymph-edema as assessed with ISL criteria | Gynecological surgery refers to surgery on the female reproductive system usually performed by gynecologists. In the domain of cancer it may include hysterectomy, ovariectomy, pelvic exenteration, salpingoophorectomy, vulvectomy and partial or complete lymphadenectomy | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - the number of patients receiving systemic therapy that develop lower limb lymph-edema as assessed with ISL criteria | Systemic therapy is a therapy that is given in addition to the primary or initial therapy to maximize its effectiveness. It can be given in adjuvant or neo-adjuvant setting. Categorical: none, taxanes, cisplatinum, immunotherapy, target therapy, anti-hormone therapy, other. | From diagnosis until 2 years after last oncologic treatment | 
| Risk factors for developing LLL - the number of patients receiving radiotherapy that develop lower limb lymph-edema as assessed with ISL criteria | Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor (for example, early stages of breast cancer). Radiation therapy is synergistic with chemotherapy, and has been used before, during, and after chemotherapy in susceptible cancers. Expressed per target volume in dose per fraction, number of fractions | From diagnosis until 2 years after last oncologic treatment | 
| Impact of LLL on QoL - EQ5D | EQ-5D is a standardised measure of health-related quality of life developed by the EuroQol Group to provide a simple, generic questionnaire for use in clinical and economic appraisal and population health surveys. EQ-5D assesses health status in terms of five dimensions of health and is considered a 'generic' questionnaire because these dimensions are not specific to any one patient group or health condition. EQ-5D can also be referred to as a patient-reported outcome (PRO) measure, because patients can complete the questionnaire themselves to provide information about their current health status and how this changes over time. 'EQ-5D' is not an abbreviation and is the correct term to use when referring to the instrument in general. Expressed as an overall measure of self-assessed health status (EQ VAS) at different time points (D0, M3, M12) | From diagnosis until 2 years after last oncologic treatment | 
| Impact of LLL on QoL - EORT qlq C30 | European Organisation for Research and Treatment of Cancer (EORTC): qlq C30: questionnaire developed by the EORTC and validated in over 100 languages, in order to assess in 30 questions the quality of life of cancer patients. | From diagnosis until 2 years after last oncologic treatment | 
| Impact of LLL on QoL - lymph-ICF-LL | Lymphoedema Functioning, Disability and Health Questionnaire for Lower Limb Lymphoedema (Lymph-ICF-LL): it is a descriptive, evaluative tool containing 28 questions about impairments in function, activity limitations, and participation restrictions in patients with lower limb lymphedema. The questionnaire has 5 domains: physical function, mental function, general tasks/household activities, mobility activities, and life domains/social life. | From diagnosis until 2 years after last oncologic treatment | 
| Impact of LLL on sexuality | Female Sexual Distress Scale Revised (FSDS-R) is a multi-dimensional self-reporting questionnaire containing 13 items to evaluate sexual distress in women. Evaluation: Percentage of patients with clinically relevant loss in sexual well-being, measured through questionnaire at baseline, 3 months, 12 months and 24 months post-treatment | From diagnosis until 2 years after last oncologic treatment | 
| Predictive value of the self-report LLL questionnaire | The self-report lower-extremity lymphedema screening questionnaire is a screening questionnaire developed to detect lower-extremity lymphedema (LEL) among normal-weight women and women with obesity. Evaluation: Number of patients with score >5 on the self-report LLL questionnaire that are diagnosed with LLL according to ISL criteria (positive predictive value) | From diagnosis until 2 years after last oncologic treatment | 
| Value of ICG fluoroscopy versus lymphoscintigraphy in detection of early stage LLL | Percentage of positive ICG fluoroscopy (image of splash, stardust or diffuse ICG pattern) corresponding with positive lympho-scintigraphy (signs of impaired lymphatic flow) or with clinical diagnosis of LLL based on ISL criteria | From diagnosis until 2 years after last oncologic treatment | 
| Inventory of time investment | Calculation of mean time investment of patients in the prevention and treatment of LLL through app-based registration | From diagnosis until 2 years after last oncologic treatment | 
| Inventory of expenses | Calculation of mean financial investment of patients in the prevention and treatment of LLL through app-based registration | From diagnosis until 2 years after last oncologic treatment | 
| Standardization of perimetric measurements | Development of standardized instructions for perimetric measurement with measurement from a fixed start point and then every 4cm to calculate leg circumference. Verification of reliability through intra- and interobserver comparison | From diagnosis until 2 years after last oncologic treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphedema of the lower limb, Gynaecologic cancer, Sexual well-being, Quality of Life, Cost-investment, Time-investment