Who and Why do Patients Report Lymphedema After Breast Cancer Treatment Without an Objective Measurable Swelling

NCT06324721 | Recruiting

• 1 other identifier: S68133
• Study Type: interventional
• Target: 230
• Locations: 1 country
• Sites: 1

Brief Summary

Breast cancer related lymphedema (BCRL) at the arm and/or trunk is an extremely dreaded complication after breast cancer treatment due to its chronicity and impact. The incidence of objective arm and trunk/ breast BCRL is declining due to the major shift into the treatment approach of breast cancer. However, many patients report a sensation of swelling without the presence of objective BCRL, referred to as subjective BCRL. Therefore, subjective BCRL is defined as the diagnosis of BCRL based on the patient's sensation of a difference in size at the arm and/or trunk without the presence of objective BCRL. At this moment, there is no clear information on the prevalence and the transitions between different BCRL states (no-subjective-objective) over time, as well as about the underlying mechanisms and contributing factors of subjective BCRL. Therefore, the investigators hypothesize that four mechanisms might be associated with the presence and severity of subjective arm or trunk/breast BCRL, including the presence and/ or severity of lymphatic (1) and sensory processing problems (nociceptive (2), neuropathic (3), and/or central sensory processing problems (4)). The investigators will set up a prospective longitudinal study with breast cancer patients to determine the prevalence of subjective and objective arm or trunk/ breast BCRL at 1, 6, and 12 month(s) post-surgery and the transitions between different BCRL states (no-subjective-objective BCRL) (AIM 1). In addition, factors related to four potential underlying mechanisms (lymphatic, nociceptive, neuropathic, and central sensory processing problems) that contribute to the occurrence of subjective BCRL in comparison to no self-reported swelling and objective BCRL will be determined (AIM 2). Furthermore, the present study will be undertaken to determine factors related to these four underlying mechanisms that contribute to the severity of subjective BCRL at arm or trunk/ breast BCRL within the group of patients with subjective BCRL at different time-points after surgery (at 1, 6, and 12 month(s) post-surgery) (AIM 3).

Conditions

Breast Cancer; Lymphedema; Sensory Processing Disorder

Keywords

lymphedema; subclinical edema; nociceptive problems; neuropathic problems; central sensory problems

Outcome Measures

Primary Outcomes (4)

• Presence of subjective arm lymphedema

  The presence of subjective arm lymphedema will be determined by the combination of two items. If self-reported swelling at arm is "yes" and objective arm BCRL is "no", then the presence of subjective arm BCRL will be defined as yes. To determine the presence of self-reported swelling at arm, we will use the Norman Questionnaire. If the patient responds ''yes'' to the item self-reported difference in the sizes of at least one of 3 sites (hand, lower arm, and upper arm), the presence of 'self-reported swelling at arm' is recorded as ''yes''. To determine the presence of objective lymphedema at arm, please see outcome 3. Unit of the outcome measure is yes/no. Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery

  Time frame up to 12 months post-surgery

• Presence of subjective trunk/ breast lymphedema

  The presence of subjective trunk/ breast lymphedema will be determined by the combination of two items. If self-reported swelling at trunk/ breast is "yes" and objective trunk/ breast BCRL is "no", then the presence of subjective trunk/ breast BCRL will be defined as yes. To determine the presence of self-reported swelling at trunk/ breast, we will use the Norman Questionnaire. If the response is ''yes'' to the item self-reported difference in the sizes of at least one of these 2 sites (trunk or breast region), the presence of ''self-reported swelling in the trunk/breast'' is recorded as ''yes.'' Unit of the outcome measure is yes/no. Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery

  Time frame up to 12 months post-surgery

• Presence of objective arm lymphedema

  4 methods are used to determine the presence of objective arm lymphedema: a) relative hand volume difference, b) relative arm volume difference, c) bioimpedance analysis, and d) bioimpedance spectroscopy at arm region If at least one of four cut-off values is present, the presence of objective arm lymphedema will be considered as yes: 1. an increase of relative hand volume difference between the affected and non-affected hands of ≥5% compared to the baseline difference OR 2. an increase of relative arm volume difference between the affected and non-affected arms of ≥5% compared to the baseline difference OR 3. Extra-cellular water ratio by Bioimpedance Analysis at affected arm of \>0.3850 OR 4. Extracellular water ratio by Bioimpedance Spectroscopy, \>6.5 change in the L-Dex score from the baseline score Unit of the outcome measure is yes/no. Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery

  Time frame up to 12 months post-surgery

• Presence of objective trunk/ breast lymphedema

  2 methods are used to determine the presence of objective trunk/breast lymphedema: a) tissue dielectric measurement, b) skin thickness measurement at trunk/breast region If one of four criteria is present, the presence of objective trunk/ breast lymphedema will be considered as yes: 1. percentage of water content ratio at the trunk ≥ 1.32 OR 2. percentage of water content ratio at the trunk ≥ 1.40 OR 3. \> 2 standard deviations (SD) from the average skin thickness in at least one reference point on the trunk compared to the reference value at pre-surgery OR 4. \> 2 SD from the average skin thickness in at least one reference point one quadrant of the affected breast compared to the reference value at pre-surgery Unit of the outcome measure is yes/no. Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery

  Time frame up to 12 months post-surgery

Secondary Outcomes (17)

• Amount of swelling at upper limb and trunk/breast

  Time frame up to 12 months post-surgery

• Severity of dermal rerouting at upper limb and trunk/breast

  Time frame up to 12 months post-surgery

• Severity of myofascial adhesions at the level of the scars

  Time frame up to 12 months post-surgery

• Severity of local muscle stiffness

  Time frame up to 12 months post-surgery

• Severity of local muscle tenderness

  Time frame up to 12 months post-surgery

Study Arms (1)

Breast cancer patients

EXPERIMENTAL

Women and men who are being diagnosed with primary unilateral non-metastatic or oligometastatic breast cancer and scheduled for breast surgery in combination with axillary lymph node dissection or sentinel node biopsy

Other: Measurements for breast cancer related lymphedema (volumetric measurements, bioimpedance spectroscopy, bioimpedance analysis, tissue dielectric constant measurements, ultrasonography); Other: Measurements for lymphatic problems (volumetric measurements, tissue dielectric measurement, lymphofluoroscopy); Other: Measurements for sensory processing problems by monofilaments, algometer, goniometer, and neurosensory analyzer

Interventions

Measurements for breast cancer related lymphedema (volumetric measurements, bioimpedance spectroscopy, bioimpedance analysis, tissue dielectric constant measurements, ultrasonography) OTHER

Assessments related to different types of breast cancer related lymphedema at arm (1. self-reported swelling at arm, 2. subjective arm lymphedema, 3. objective arm lymphedema) using the Norman questionnaire, volume measurements (volumetry and perimetry), bioimpedance spectroscopy, and bioimpedance analysis Assessments related to different types of breast cancer related lymphedema at trunk/ breast (1. self-reported swelling at trunk/ breast, 2. subjective trunk/ breast lymphedema, 3. objective trunk/ breast lymphedema) using the Norman questionnaire, tissue dielectric measurements, and ultrasonography

Breast cancer patients

Measurements for lymphatic problems (volumetric measurements, tissue dielectric measurement, lymphofluoroscopy) OTHER

Clinical assessments related to lymphatic problems (1. amount of swelling at arm by relative arm volume difference, 2. amount of swelling at trunk by percentage water ratio, 3. severity of dermal rerouting at upper limb and trunk by lymphofluoroscopy (i.e., near-infrared fluorescence imaging device)

Breast cancer patients

Measurements for sensory processing problems by monofilaments, algometer, goniometer, and neurosensory analyzer OTHER

Clinical measurements related to nociceptive, neuropathic and central sensory problems based on the Quantitative Sensory Testing principles using different devices algometer, goniometer, standardized set of monofilaments, and neurosensory analyzer

Breast cancer patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• adults (men and women) who are ≥ 18 years of age
• diagnosed with primary unilateral non-metastatic or oligometastatic breast cancer
• scheduled for surgery (mastectomy or breast conserving surgery; in combination with axillary lymph node dissection or sentinel node biopsy)
• able to read, understand, and speak Dutch
• have voluntary written informed consent of the patient

You may not qualify if:

• distant metastases
• planned bilateral lymph node surgery
• oedema of the arm from another cause
• an allergy to iodine or Indocyanine Green (ICG), or
• physically or mentally unable to participate throughout the entire duration of the study

Sponsors & Collaborators

• Universitaire Ziekenhuizen KU Leuven: lead
• Universiteit Antwerpen: collaborator

Study Sites (1)

University Hospitals of Leuven, center for lymphedema

Leuven, Vlaams-Brabant, 3000, Belgium

RECRUITING

Related Publications (9)

• Gursen C, Dylke ES, Moloney N, Meeus M, De Vrieze T, Devoogdt N, De Groef A. Self-reported signs and symptoms of secondary upper limb lymphoedema related to breast cancer treatment: Systematic review. Eur J Cancer Care (Engl). 2021 Sep;30(5):e13440. doi: 10.1111/ecc.13440. Epub 2021 Mar 18.

  PMID: 33733550 BACKGROUND

• Svensson BJ, Dylke ES, Ward LC, Black DA, Kilbreath SL. Screening for breast cancer-related lymphoedema: self-assessment of symptoms and signs. Support Care Cancer. 2020 Jul;28(7):3073-3080. doi: 10.1007/s00520-019-05083-7. Epub 2019 Oct 22.

  PMID: 31641870 BACKGROUND

• De Groef A, Devoogdt N, Gursen C, Moloney N, Warpy V, Daelemans J, Dams L, Haenen V, Van der Gucht E, Heroes AK, De Vrieze T, Dylke E. Correction to: Sensory signs and symptoms in women with self-reported breast cancer-related lymphedema: a case-control study. J Cancer Surviv. 2022 Dec;16(6):1508-1509. doi: 10.1007/s11764-021-01125-4. No abstract available.

  PMID: 34716888 BACKGROUND

• Fu MR, Axelrod D, Cleland CM, Qiu Z, Guth AA, Kleinman R, Scagliola J, Haber J. Symptom report in detecting breast cancer-related lymphedema. Breast Cancer (Dove Med Press). 2015 Oct 15;7:345-52. doi: 10.2147/BCTT.S87854. eCollection 2015.

  PMID: 26527899 BACKGROUND

• Sackey H, Johansson H, Sandelin K, Liljegren G, MacLean G, Frisell J, Brandberg Y. Self-perceived, but not objective lymphoedema is associated with decreased long-term health-related quality of life after breast cancer surgery. Eur J Surg Oncol. 2015 Apr;41(4):577-84. doi: 10.1016/j.ejso.2014.12.006. Epub 2015 Jan 13.

  PMID: 25659877 BACKGROUND

• Terada M, Yoshimura A, Sawaki M, Hattori M, Naomi G, Kotani H, Adachi Y, Iwase M, Kataoka A, Sugino K, Mori M, Horisawa N, Ozaki Y, Iwata H. Patient-reported outcomes and objective assessments with arm measurement and bioimpedance analysis for lymphedema among breast cancer survivors. Breast Cancer Res Treat. 2020 Jan;179(1):91-100. doi: 10.1007/s10549-019-05443-1. Epub 2019 Sep 18.

  PMID: 31535321 BACKGROUND

• Sayko O, Pezzin LE, Yen TW, Nattinger AB. Diagnosis and treatment of lymphedema after breast cancer: a population-based study. PM R. 2013 Nov;5(11):915-23. doi: 10.1016/j.pmrj.2013.05.005. Epub 2013 May 17.

  PMID: 23684778 BACKGROUND

• McLaughlin SA, Wright MJ, Morris KT, Sampson MR, Brockway JP, Hurley KE, Riedel ER, Van Zee KJ. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: patient perceptions and precautionary behaviors. J Clin Oncol. 2008 Nov 10;26(32):5220-6. doi: 10.1200/JCO.2008.16.3766. Epub 2008 Oct 6.

  PMID: 18838708 BACKGROUND

• Gursen C, Meeus M, Verbeelen K, Vets N, Spincemaille L, Smeets A, Thomis S, Fieuws S, Vanderheyden H, Gebruers N, Tjalma W, Johansson K, Keeley V, De Groef A, Devoogdt N. LymphSens study: the enigma of subjective lymphoedema - how often and why do patients report lymphoedema after breast cancer treatment without an objective measurable swelling? The role of lymphatic and sensory processing problems: a protocol for a multicentre prospective longitudinal study. BMJ Open. 2025 Jun 8;15(6):e099990. doi: 10.1136/bmjopen-2025-099990.

  PMID: 40484423 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Lymphedema

Interventions

Weights and Measures; High-Energy Shock Waves

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Lymphatic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Investigative Techniques; Ultrasonic Waves; Sound; Radiation, Nonionizing; Radiation; Physical Phenomena

Study Officials

• Nele Devoogdt, Prof. Dr.

  KU Leuven

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nele Devoogdt, Prof. Dr.

CONTACT

003216342515; nele.devoogdt@uzleuven.be

Ceren Gursen, Dr

CONTACT

003216325815; ceren.guersen@kuleuven.be

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: Prospective cohort study

Study Record Dates

• First Submitted: March 12, 2024
• First Posted: March 22, 2024
• Study Start: March 26, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027
• Last Updated: January 29, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1)