Development of a Clinical Screening, Diagnostic and Evaluation Tool for Patients With Lower Limb Lymphedema: Aim 2

Study Overview
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Brief Summary
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Lymphedema is a chronic, debilitating disorder characterized by abnormal tissue swelling, adipose deposition and tissue fibrosis, resulting from disruption, blockage, or genetic abnormalities of the lymphatic system. Secondary lymphedema is an acquired lymphedema due to trauma, surgery, radiotherapy or infection among others resulting in a decreased transport capacity of the lymphatic system. This can be combined with an additional load on the lymphatic system due to obesity, venous hypertension or a wound, among others. Advances in oncologic treatment have led to an ever-increasing number of cancer survivors over time. As a result, morbidities related to this treatment (such as secondary lymphedema) are likely to increase too. Risk factors for the development of LLL after treatment for (gynaecological) cancer are: pelvic and para-aortic lymphadenectomy, the number of pelvic lymph nodes removed, adjuvant radiotherapy, adjuvant chemotherapy, increasing BMI/ BMI ≥25 kg/m², lymphocyst formation, increasing age, increasing time since surgery and insufficient physical activity level. To the investigators knowledge, no evidence exists regarding which (combination of) measuring methods are most sensitive to detect early lymphedema at the lower limbs after the treatment of cancer. Thresholds for identifying subclinical edema on one or both lower limbs are lacking. Therefore the investigators want to develop a screening set for patients at risk for developing LLL. Which measurement method (and which criterion) shows the best diagnostic accuracy in screening patients at risk for LLL after cancer treatment? And: What is the added value of combining different measurement methods in terms of diagnostic accuracy?

Official Title
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Development of a Clinical Screening, Diagnostic and Evaluation Tool for Patients With Lower Limb Lymphedema: Development of a Screening Set for Patients at Risk for Developing LLL

Conditions
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Lower Limb Lymphedema

Intervention / Treatment
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* Diagnostic Test: clinical assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a diagnosis of skin melanoma (at the level of the lower limb, at least cancer stage 3), gynecological cancer, uro-genital cancer that will receive surgery (sentinel lymph node biopsy and/or (para-aortic/inguinal/pelvic) lymph node dissection) Exclusion Criteria: Pregnant participants Presence of chronic venous insufficiency C4, C5, C6; deep venous thrombosis; post-thrombotic syndrome Presence of skin infections of wounds at the level of the lower limbs at the moment of inclusion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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 |
| --- | --- |
| lymph node dissection for treatment of urogenital, gynaelogical or skin cancer<br>Patients with any type of skin melanoma (at the level of the lower limb), urogenital or gynaecological cancer scheduled for lymph node dissection | Diagnostic Test: clinical assessment<br>* screening of patients at risk for developing unilateral or bilateral lower limb lymphedema<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity of reliable and clinical feasible measurement methods regarding the screening of patients at risk for developing unilateral or bilateral LLL | Sensitivity of reliable and clinical feasible measurement methods (resulted from aim 1: NCT05269264) regarding the screening of patients at risk for developing unilateral or bilateral LLL at 6 weeks, 6, and 12 months post-surgery | up to 12 months post-surgery | 
| Specificity of reliable and clinical feasible measurement methods regarding the screening of patients at risk for developing unilateral or bilateral LLL | Specificity of reliable and clinical feasible measurement methods (resulted from aim 1: NCT05269264) regarding the screening of patients at risk for developing unilateral or bilateral LLL at 6 weeks, 6, and 12 months post-surgery | up to 12 months post-surgery | 
| Diagnostic accuracy of reliable and clinical feasible measurement methods regarding the screening of patients at risk for developing unilateral or bilateral LLL | Diagnostic accuracy of reliable and clinical feasible measurement methods (resulted from aim 1: NCT05269264) regarding the screening of patients at risk for developing unilateral or bilateral LLL at 6 weeks, 6, and 12 months post-surgery | up to 12 months post-surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prognostic value of 'baseline age' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Age (years) will be self-reported through interview. | 6 weeks post-surgery | 
| Prognostic value of 'baseline age' for the development of bilateral lower limb lymphoedema at 12 months post-surgery. | Dependent variable = presence of lower limb lymphoedema Independent variable= Age (years) will be self-reported through interview. | 12 months post-surgery | 
| Prognostic value of ' Baseline physical activity level' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Baseline physical activity level : will be assessed with the International Physical Activity Questionnaire (IPAQ). The IPAQ is a 27-item self-reported measure of physical activity for use with individual adult patients aged 15 to 69 years old. Results can be reported in categories (low activity levels, moderate activity levels or high activity levels) or as a continuous variable (MET minutes a week). MET minutes represent the amount of energy expended carrying out physical activity. | 6 weeks post-surgery | 
| Prognostic value of ' Baseline physical activity level' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Baseline physical activity level : will be assessed with the International Physical Activity Questionnaire (IPAQ). The IPAQ is a 27-item self-reported measure of physical activity for use with individual adult patients aged 15 to 69 years old. Results can be reported in categories (low activity levels, moderate activity levels or high activity levels) or as a continuous variable (MET minutes a week). MET minutes represent the amount of energy expended carrying out physical activity. | 12 months post-surgery | 
| Prognostic value of ' Baseline educational level' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Educational level: will be self-reported through interview. | 6 weeks post-surgery | 
| Prognostic value of ' Baseline educational level' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Educational level: will be self-reported through interview. | 12 months post-surgery | 
| Prognostic value of ' Baseline BMI' for the development of bilateral lower limb lymphoedema at 6 weeks post- surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= baseline Body Mass Index | 6 weeks post- surgery | 
| Prognostic value of ' Baseline BMI' for the development of bilateral lower limb lymphoedema at 12 months post- surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= baseline Body Mass Index | 12 months post- surgery | 
| Prognostic value of ' Baseline comorbidities' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= baseline comorbidities Comorbidities will be reported through a self-developed co-morbidity questionnaire, based on IDEWE questionnaire. | 6 weeks post-surgery | 
| Prognostic value of ' Baseline comorbidities' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= baseline comorbidities Comorbidities will be reported through a self-developed co-morbidity questionnaire, based on IDEWE questionnaire. | 12 months post-surgery | 
| Prognostic value of 'Type of cancer' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Type of cancer Information regarding the type of cancer is collected by exploring the patient's medical file. | 6 weeks post-surgery | 
| Prognostic value of 'Type of cancer' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Type of cancer Information regarding the type of cancer is collected by exploring the patient's medical file. | 12 months post-surgery | 
| Prognostic value of 'Tumor stage' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Tumor stage Information regarding the tumor stage of is collected by exploring the patient's medical file. | at 6 weeks post-surgery | 
| Prognostic value of 'Tumor stage' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Tumor stage Information regarding the tumor stage of is collected by exploring the patient's medical file. | 12 months post-surgery | 
| Prognostic value of 'Lymph node stage' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Lymph node stage Information regarding the lymph node stage of is collected by exploring the patient's medical file. | 6 weeks post-surgery | 
| Prognostic value of 'Lymph node stage' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable= Lymph node stage Information regarding the lymph node stage of is collected by exploring the patient's medical file. | 12 months post-surgery | 
| Prognostic value of 'Number of positive lymph nodes' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable=Number of positive lymph nodes: is collected through the patient's medical file. | 6 weeks post-surgery | 
| Prognostic value of 'Number of positive lymph nodes' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Dependent variable = presence of lower limb lymphoedema Independent variable=Number of positive lymph nodes: is collected through the patient's medical file. | 12 months post-surgery | 
| Prognostic value of 'Postoperative complications' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Information regarding the complications related to the surgery as well as adjuvant therapies is collected. Surgical complications will be assessed according to the Clavien-Dindo Classification of Surgical Complications. | 6 weeks post-surgery | 
| Prognostic value of 'Postoperative complications' for the development of lower limb lymphoedema at 12 months post-surgery | Information regarding the complications related to the surgery as well as adjuvant therapies is collected. Surgical complications will be assessed according to the Clavien-Dindo Classification of Surgical Complications. | 12 months post-surgery | 
| Prognostic value of 'Type of lymph node dissection' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Cancer treatment characteristics are collected (i.e. type of surgery, type of lymph node dissection, number of lymph nodes removed, presence of postoperative drain, number of positive lymph nodes, adjuvant therapies; by exploring the patient's medical file. Type of lymph node dissection: Limited- Standard- Extended- Super extended | 6 weeks post-surgery | 
| Prognostic value of 'Type of lymph node dissection' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Cancer treatment characteristics are collected (i.e. type of surgery, type of lymph node dissection, number of lymph nodes removed, presence of postoperative drain, number of positive lymph nodes, adjuvant therapies; by exploring the patient's medical file. Type of lymph node dissection: Limited- Standard- Extended- Super extended | 12 months post-surgery | 
| Prognostic value of 'Number of lymph nodes removed' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Cancer treatment characteristics are collected (i.e. type of surgery, type of lymph node dissection, number of lymph nodes removed, presence of postoperative drain, number of positive lymph nodes, adjuvant therapies; by exploring the patient's medical file. | 6 weeks post-surgery | 
| Prognostic value of 'Number of lymph nodes removed' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Cancer treatment characteristics are collected (i.e. type of surgery, type of lymph node dissection, number of lymph nodes removed, presence of postoperative drain, number of positive lymph nodes, adjuvant therapies; by exploring the patient's medical file. | 12 months post-surgery | 
| Prognostic value of 'Adjuvant Radiotherapy' for the development of bilateral lower limb lymphoedema at 6 weeks post-surgery | Cancer treatment characteristics , including adjuvant radiotherapy are collected; by exploring the patient's medical file. | 6 weeks post-surgery | 
| Prognostic value of 'Adjuvant Radiotherapy' for the development of bilateral lower limb lymphoedema at 12 months post-surgery | Cancer treatment characteristics , including adjuvant radiotherapy are collected; by exploring the patient's medical file. | 12 months post-surgery | 
| Incidence rate of unilateral and bilateral LLL at 6 weeks post-surgery | Calculation of the proportion of patients with leg (or foot) lymphedema, defined as 5.0% or more increase of the leg (or foot) volume in each leg (or foot), at a certain time point, compared to the volumes at baseline; OR patients with a score of at least 5 out of 52 on the detect-OL questionnaire in case it is clearly indicated whether symptoms are present in one or both legs (in order to be able to categorize patients to the unilateral LLL or bilateral LLL group). Additionally, the proportion of presence of LLL in patients having received a lymph node dissection due to gynaecological cancer vs. due to urogenital cancer vs. due to skin melanoma will be compared. The distribution of LLL (unilateral vs. bilateral, regions of the lower limb) will be encountered and compared. | 6 weeks post-surgery | 
| Incidence rate of unilateral and bilateral LLL at 6 months post-surgery | Calculation of the proportion of patients with leg (or foot) lymphedema, defined as 5.0% or more increase of the leg (or foot) volume in each leg (or foot), at a certain time point, compared to the volumes at baseline; OR patients with a score of at least 5 out of 52 on the detect-OL questionnaire in case it is clearly indicated whether symptoms are present in one or both legs (in order to be able to categorize patients to the unilateral LLL or bilateral LLL group). Additionally, the proportion of presence of LLL in patients having received a lymph node dissection due to gynaecological cancer vs. due to urogenital cancer vs. due to skin melanoma will be compared. The distribution of LLL (unilateral vs. bilateral, regions of the lower limb) will be encountered and compared. | 6 months post-surgery | 
| Incidence rate of unilateral and bilateral LLL at 12 months post-surgery | Calculation of the proportion of patients with leg (or foot) lymphedema, defined as 5.0% or more increase of the leg (or foot) volume in each leg (or foot), at a certain time point, compared to the volumes at baseline; OR patients with a score of at least 5 out of 52 on the detect-OL questionnaire in case it is clearly indicated whether symptoms are present in one or both legs (in order to be able to categorize patients to the unilateral LLL or bilateral LLL group). Additionally, the proportion of presence of LLL in patients having received a lymph node dissection due to gynaecological cancer vs. due to urogenital cancer vs. due to skin melanoma will be compared. The distribution of LLL (unilateral vs. bilateral, regions of the lower limb) will be encountered and compared. | 12 months post-surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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screening, urogenital cancer, gynaecological cancer, skin cancer, lymph node dissection