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

Breast Cancer Clinical Trial

— LymphSens  

Official title:

The Enigma of Subjective Lymphedema: Why do Patients Report Lymphedema After Breast Cancer Treatment Without an Objective Measurable Swelling? The Role of Sensory Processing and Subclinical Lymphedema

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06324721
• Other study ID #: S68133
• Status: Recruiting
• Phase: N/A
• Start date: March 26, 2024
• Est. completion date: March 2027

Study information

• Verified date: April 2024
• Source: Universitaire Ziekenhuizen KU Leuven
• Contact: Nele Devoogdt, Prof. Dr.
• Phone: 003216342515
• Email: nele.devoogdt[@]uzleuven.be
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Breast cancer related lymphedema (BCRL) is due to its chronicity and impact an extremely dreaded complication after breast cancer treatment. The prevalence rate of objective arm and trunk/ breast BCRL is declining due to the major shift into the treatment approach of breast cancer. However, the prevalence rate of subjective arm and trunk/ breast BCRL is much higher than that of objective BCRL. 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 any objectively measurable swelling. At this moment, it is not clear how many breast cancer patients experience subjective arm or trunk/breast BCRL and what the underlying mechanisms may be. Therefore, the investigators hypothesize that four mechanisms might be associated with the presence and the severity of subjective arm or trunk/breast BCRL, including sensory processing problems (1. nociceptive and/or 2. neuropathic and/or 3. central) and the presence of disturbed lymphatic transport without clinical manifestation (4. subclinical BCRL). 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 the different types of BCRL and to compare the amount of swelling at arm or trunk/ breast, the presence or severity of subclinical BCRL and peripheral and central sensory processing problems between patients with different types of BCRL. In addition, the present study will be undertaken to determine the contributing factors to the severity of subjective 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 230
• Est. completion date: March 2027
• Est. primary completion date: March 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Diagnosis of primary unilateral breast cancer or oligo-metastatic breast cancer

2. Patients scheduled for surgery (mastectomy or breast conserving surgery; in combination with axillary lymph node dissection or sentinel node biopsy)

3. Able to read, understand, and speak Dutch

4. Having voluntary written informed consent of the participant prior to any screening procedures.

Exclusion Criteria:

1. Patients with widespread distance metastasis, previous breast surgery, or planned bilateral surgery

2. Oedema of the arm from other cause

3. Allergy for iodine, sodium iodine, or Indocyanine Green

4. Physically or mentally unable to participate during the entire duration of the study.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Lymphedema
• Sensory Processing Disorder

Intervention

Other:
• Oedema measurements and sensory evaluations
assessments of different types of arm and trunk/ breast oedema (self-reported swelling at arm and trunk/ breast, subjective arm lymphedema, subjective trunk/ breast lymphedema, objective arm lymphedema, objective trunk/ breast lymphedema)) clinical assessments for subclinical lymphedema and nociceptive, neuropathic and central sensory problems

Locations

Country	Name	City	State
Belgium	University Hospitals of Leuven, center for lymphedema	Leuven	Vlaams-Brabant

Sponsors (2)

Lead Sponsor	Collaborator
Universitaire Ziekenhuizen KU Leuven	Universiteit Antwerpen

Country where clinical trial is conducted

Belgium, 

References & Publications (8)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Presence of self-reported swelling at arm	Assessed by a question on the self-reported difference in the sizes of the hands, lower arms or upper arms.; If the score is "0" on 3 sites, the patient is considered as having 'no self-reported swelling at arm'; =1 as having 'self-reported swelling at arm'.; 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
Primary	Presence of self-reported swelling at trunk	Assessed by a question on the self-reported difference in the sizes of the trunk. If the score is "0" on this question, the patient is considered as having 'no self-reported swelling at trunk'; =1 as having 'self-reported swelling at trunk'.; 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
Primary	Presence of self-reported swelling at breast	Assessed by a question on the self-reported difference in the sizes of the breast. If the score is "0" on this question, the patient is considered as having 'no self-reported swelling at breast'; =1 as having 'self-reported swelling at breast'.; 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
Primary	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.; 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
Primary	Presence of subjective trunk lymphedema	The presence of subjective trunk lymphedema will be determined by the combination of two items. If self-reported swelling at trunk is "yes" and objective trunk BCRL is "no", then the presence of subjective trunk BCRL will be defined 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
Primary	Presence of subjective breast lymphedema	The presence of subjective breast lymphedema will be determined by the combination of two items. If the presence of self-reported swelling at breast is "yes" and the presence of objective breast BCRL is "no", then the presence of subjective breast BCRL will be defined 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
Primary	Relative hand volume difference	The relative volume difference between the affected and non-affected hands will be determined using the water displacement method with volumeter.; Unit of the outcome measure is %.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Primary	Relative arm volume difference	The relative volume difference between the affected and non-affected arms will be determined using the water displacement method with volumeter.; Unit of the outcome measure is %.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Primary	Extra-cellular water ratio by Bioimpedance Analysis	Extra-cellular water ratio will be determined by the bioimpedance analysis device.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Primary	Extra-cellular water ratio by Bioimpedance Spectroscopy	Extra-cellular water ratio will be determined by the bioimpedance spectroscopy device.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Primary	Presence of objective arm lymphedema	If one of four criteria is present, the presence of objective arm lymphedema will be considered as yes: an increase of relative hand volume difference between the affected and non-affected hands of =5% (outcome 7) OR; an increase of relative arm volume difference between the affected and non-affected arms of =5% (outcome 8) OR; Extra-cellular water ratio by Bioimpedance Analysis at affected arm of >0.3850 (outcome 9) OR; Extracellular water ratio by Bioimpedance Spectroscopy at affected arm versus unaffected arm >10.0; 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
Primary	Relative percentage of water content (PWC) ratio	The relative percentage of water content (PWC) ratio at the affected trunk and breast will be measured by the skin moisture meter device.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Primary	Skin thickness	Skin thickness at the lateral side of the trunk, chest wall, and breast by two dimensional conventional ultrasonography (with B mode) will be determined.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Primary	Presence of objective trunk lymphedema	If one of two criteria is present, the presence of objective trunk lymphedema will be considered as yes: percentage of water content ratio at the trunk = 1.32 (outcome 12) OR; > 2 standard deviations (SD) from the average skin thickness in at least one reference points on the trunk or chest wall (outcome 13).; 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
Primary	Presence of objective breast lymphedema	If one of two criteria is present, the presence of objective breast lymphedema will be considered as yes: percentage of water content ratio at the breast = 1.32 (outcome 12) OR; > 2 standard deviations (SD) from the average skin thickness in at least one reference points on quadrants of the affected breast (outcome 13).; 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	Dermal rerouting score at arm	Lymphofluoroscopy will be used. Indocyanine green (ICG)/ aqua is injected in the patient's hand; linear (normal) and dermal rerouting patterns are visualized. The arm is divided into 11 areas and is scored between 0 and 3: 0 (normal pattern), 1 (splash pattern), 2 (stardust pattern), and 3 (diffuse pattern).; Total score is between 0 and 33.; Assessment at 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Dermal rerouting score at trunk	Lymphofluoroscopy will be used. Indocyanine green (ICG)/ aqua is injected in the patient's hand; linear (normal) and dermal rerouting patterns are visualized. The trunk is divided into 3 areas and is scored between 0 and 3: 0 (normal pattern), 1 (splash pattern), 2 (stardust pattern), and 3 (diffuse pattern).; Total score is between 0 and 9.; Assessment at 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Severity of myofascial adhesions	The evaluation tool for Myofascial Adhesions in Patients after Breast Cancer (MAP-BC evaluation tool): assessed at 2 locations (i.e., axillary scar, breast or mastectomy scar). Each location is palpated for adhesions at 3 levels (i.e., skin, superficial, and deep) on a 4-points scale (0- no restriction, 1-limited restriction, 2-hard restriction, and 3-very stiff).; Total score ranges between 0 - 18.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Myofascial tissue stiffness	Myofascial tissue stiffness will be evaluated at the pectoralis major, upper trapezius, infraspinatus, and teres major muscles.; Unit of the outcome measure is Newton/ meter.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Pressure pain thresholds	Pressure pain thresholds will be evaluated using digital algometer on affected and non-affected pectoralis major, upper trapezius, infraspinatus, and teres major muscles and non-affected tibialis anterior.; Unit of the outcome measure is kilogram per square centimeter (kg/cm2).; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Arm abduction range	Arm abduction range will be evaluated by the digital goniometer.; Unit of the outcome measure is degree.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Presence of neuropathic pain	The presence of neuropathic pain will be evaluated by the Douleur neuropathique en 4 questions (DN4). DN4 consists of interview and examination parts. Interview part: seven items about pain descriptors. Examination part: three items about the hypoesthesia to touch and pinprick, and the presence or severity of pain by the application of brushing.; Total score ranges between 0 - 10.; The presence of neuropathic pain is "yes" if the total score of DN4 is =4 .; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Mechanical detection thresholds	Mechanical detection thresholds will be determined by using nylon monofilaments at affected inner upper arm, lateral trunk, and non-affected tibialis anterior muscle.; Score is between 0.25 - 512 millinewton (mN).; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Thermal detection and pain thresholds	Thermal detection and pain thresholds will be assessed by the Thermotest device (TSA-2 Neurosensory Analyser) at affected inner upper arm, lateral trunk, and non-affected tibialis anterior muscle.; Score is between 0 and 50 centigrade degree.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Sensory acuity	Sensory acuity will be evaluated using aesthesiometer at the affected inner side of upper arm and lateral side of the trunk.; Score is between 0 - 100 millimeter.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Dysfunctional inhibitory pain mechanism	A cold pressure test will be performed to test dysfunctional inhibitory pain mechanism.; The test (pressure pain threshold on the non-affected tibialis anterior muscle) and conditioning stimulus (cold stimulus on non-affected hand) will be applied.; When the second pressure pain threshold (i.e., test stimulus) is similar or lower than the first, the presence of dysfunctional inhibitory pain mechanism is accepted 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
Secondary	Enhanced facilitating mechanism	Temporal summation assessment will be performed using a 26 g monofilament. Repetitive 30 stimuli will be applied at affected lateral trunk and non-affected tibialis anterior muscle. Perceived intensity of stimulus will be assessed between 0 and 10.; If perceived intensity of stimulus is increased >2, enhanced facilitating mechanism will be accepted as "yes".; Unit of measurement 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	Body perception	Body perception will be evaluated by the Fremantle Upper Limb Awareness Questionnaire.; This questionnaire evaluates neglect-like symptoms, reduced sensory acuity, and perceived limb size and consists of 9 items. Each item is scored on a 5-point Likert scale from 0 (never) to 4 (always).; Total score ranges between 0 - 63.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery.	Time frame up to 12 months post-surgery
Secondary	Severity of subjective arm lymphedema	Severity of subjective arm lymphedema will be determined based on the severity of the difference in the size of 3 sites (hand, lower arm, and upper arm) by two items: 1) frequency with "0: not applicable to 4: almost always" and 2) severity with "0: not applicable to 3: very noticeable".; Total score ranges between 0 and 21.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery
Secondary	Severity of subjective trunk lymphedema	The severity of subjective trunk BCRL will be determined by the severity of the difference in the size of trunk by two items: 1) frequency with "0: not applicable to 4: almost always" and 2) severity with "0: not applicable to 3: very noticeable".; Total score is between 0 and 7.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery.	Time frame up to 12 months post-surgery
Secondary	Severity of subjective breast lymphedema	The severity of subjective breast BCRL will be determined by the severity of the difference in the size of breast by two items: 1) frequency with "0: not applicable to 4: almost always" and 2) severity with "0: not applicable to 3: very noticeable".; Total score is between 0 and 7.; Assessment at pre-surgery (baseline) and 1 month, 6 months, and 12 months post-surgery	Time frame up to 12 months post-surgery