Clinical trial NCT05469945: Lymphedema After Gyneco-oncologic Treatment
Official title: Lower Limb Lymphedema After Gyneco-oncologic Therapy: Can we Prevent Irreversible Lymphedema?
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Lymphedema
Genital Neoplasm
Keywords: Lymphedema of the lower limb
Gynaecologic cancer
Sexual well-being
Quality of Life
Cost-investment
Time-investment
Lead sponsor: University Hospital, Ghent
Sponsor class: OTHER
Collaborators: name: University Hospital, Louvain
name: Kom Op Tegen Kanker
First posted: 2022-07-22
Enrollment: 218
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized controlled trial evaluating the added value of CC2 compressive garments in stage 0-1 LLL
Primary purpose: TREATMENT

Brief summary: 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 between diagnosis until maximum 2 weeks after start of the first treatment. They will be 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: 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.

Sample size calculation:

The sample size is calculated for the interventional sub-cohort, to have at least 80% power to detect a difference between the compression group and the control group for progression of lymphedema. An alpha has been set equal to 0.05.

Sample size calculation is based on evaluation at year 1. No longitudinal analysis is foreseen as primary analysis, but this could be included as a secondary analysis using a GEE analysis.

To detect a difference, in the interventional sub-cohort 109 subjects are required per group (2\*109=218 subjects in total for the two groups) to have at least 80% power. If 66% of the patients in the observational cohort will meet the inclusion criteria for the interventional randomized trial, at least 330 (=218/0.66) patients should be included in the observational cohort. To correct for drop out we planned to include 400 patients. This number is feasible within the planned recruitment period of 18-24 months. If the number of subjects would be reached before the end of the planned recruitment period, recruitment will be stopped at 400 patients. If the number is not attained, the recruitment period will be prolonged. If the number of 218 subjects is reached in the interventional sub-cohort, randomization will be stopped and analysis starts. However, the observational cohort will continue accrual until 400 subjects are reached.

We assume a difference in true transition rates (T1 to T3) in both study arms, with 0.4 in the interventional group versus 0.75 in the control group. The recruitment of 109 patients in each treatment arm would allow the assessment of benefit of the intervention with 80% power, based on the 95% two-sided confidence interval approach for the differences in two independent proportions.

Eligibility criteria: 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 administered \> 2 weeks before
* Clinical signs and symptoms of lymphedema present (ISL stage 0 or higher) at the moment of intake

Primary outcomes:
measure: Incidence rate of LLL
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Incidence rate of transition from stage 0-1 LLL to stage 2-3 LLL in randomized subgroup
timeFrame: From transition to stage 0-1 LLL until 1 year after
Secondary outcomes:
measure: Timing of development of LLL
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - per age category the number of patients that develop lower limb lymph-edema as assessed with ISL criteria
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - weight
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - height
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: 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)
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: 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
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - Marital status
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - obstetrical status
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - education status
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - employment status
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - smoking status
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - pack-years
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - alcohol intake
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - physical appearance
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - household income category
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - number of patients with contact allergy that develop lower limb lymph-edema as assessed with ISL criteria
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: 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
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - pain score
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - tumor stage (TNM)
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - tumor stage (FIGO)
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: 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
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - the number of patients receiving systemic therapy that develop lower limb lymph-edema as assessed with ISL criteria
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Risk factors for developing LLL - the number of patients receiving radiotherapy that develop lower limb lymph-edema as assessed with ISL criteria
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Impact of LLL on QoL - EQ5D
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Impact of LLL on QoL - EORT qlq C30
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Impact of LLL on QoL - lymph-ICF-LL
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Impact of LLL on sexuality
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Predictive value of the self-report LLL questionnaire
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Value of ICG fluoroscopy versus lymphoscintigraphy in detection of early stage LLL
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Inventory of time investment
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Inventory of expenses
timeFrame: From diagnosis until 2 years after last oncologic treatment
measure: Standardization of perimetric measurements
timeFrame: From diagnosis until 2 years after last oncologic treatment
Other outcomes:
measure: Tolerance of and compliance to preventive compressive garments as assessed with the ICC compression questionnaire
timeFrame: From transition to stage until 1 year after
measure: Impact of preventive compressive garments on evolution of leg volume
timeFrame: From transition to stage until 1 year after
measure: Impact of preventive compressive garments on patient's time investment, including putting on and of compressive garments, washing compressive clothing, skin care...
timeFrame: From transition to stage until 1 year after
measure: Impact of preventive compressive garments on financial investment, including reimbursed as well as out-of-pocket patient cost for compressive stockings, supplementary tools, nursing aid...
timeFrame: From transition to stage until 1 year after
Locations:
city: Ghent
country: Belgium
facility: Ghent University Hospital, Dept. Radiotherapy-Oncology
city: Louvain
country: Belgium
facility: University Hospital, Louvain
Study officials:
affiliation: University Hospital, Ghent
name: Chris Monten, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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