The Effectiveness of Lymphatic Bypass Supermicrosurgery (ELYBS)

The Effectiveness of Lymphatic Bypass Supermicrosurgery for Primary Lymphedema Prevention After Breast Cancer Axillary Lymph Node Dissection: a Randomized Controlled Study

This study evaluate the effectiveness of lymphatic bypass supermicrosurgery (LBS) and axillary lymph node dissection (ALND) compare to ALND alone to prevent breast cancer treatment-related lymphedema (BCRL).

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer Related Lymphedema; Lymphedema Arm
• Intervention / Treatment: Procedure: Lymphatic Bypass Supermicrosurgery

Detailed Description

In the intervention group, LBS was performed after ALND with the intima-to-intima coaptation using the supermicrosurgery technique. The anastomosis is done between the afferent lymphatic vessel to the recipient's vein, or if possible, from the afferent to the efferent lymphatic vessel. The upper extremity lymphedema (UEL) index and indocyanine green (ICG) lymphography are utilized to evaluate the development of lymphedema.

• Study Type: Interventional
• Enrollment (Estimated): 140
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Indonesia
  • Jakarta, Indonesia, 11420
    • Dharmais National Cancer Center Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Breast cancer patient aged >18 years old
• Breast cancer patient with clinically ALNs metastases (cN1 or cN2).
• Breast cancer patient with no clinical metastasis and tumor size ≥5cm or no sentinel lymph node biopsy facility in the hospital.
• Any breast cancer patients that receive neoadjuvant systemic therapy.

Exclusion Criteria:

• Stage IV breast cancer patients who do not show clinical and radiological improvement after primary systemic therapy.
• Breast cancer patients with previous surgeries such as mastectomy, axillary lymph node biopsy, sentinel lymph node biopsy (SLNB), and ALND.
• Breast cancer patients with prior breast, chest wall, axillary, or neck radiotherapy.
• Breast cancer patients with preoperative lymphatic system abnormality detected by ICG lymphography.
• Breast cancer patients with iodine allergy, asthma, decreased kidney function, pregnancy, and lactation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Axillary lymph node dissection with LBS; 70 subjects will be needed for each group. A standard mastectomy or lumpectomy incision is made and ALND will be done in the same incision. The lymphatic vessels and lymph nodes will be resected using a near-infrared (NIR) camera. To locate lymphatic vessels, a microscope with ICG lymphography navigation is employed. LBS was performed by making intima-to-intima anastomosis between the afferent lymphatic vessels and the recipient's veins, or to the efferent lymphatic vessels. The anastomosis patency will be assessed by observing the ICG fluorescent flow. After surgery, follow-up will be done every 2 months and every 3 months in the second year. UEL index, ICG lymphography, and quality of life evaluation will be done. The cumulative incidence of BCRL, the free survival time of BCRL, and subclinical lymphedema (SCL) progression will be reported descriptively. BCRL risk factors and collateral lymphatic pathway will be observed as well.	Procedure: Lymphatic Bypass Supermicrosurgery; Axillary Lymph Node Dissection with Lymphatic Bypass Supermicrosurgery
No Intervention: Axillary lymph node dissection without LBS; 70 subjects will be needed for each group. A standard mastectomy or lumpectomy incision is made and ALND will be done in the same incision. After primary breast cancer removal, a standard ALND level I, II, and if necessary, level III is performed. After surgery, follow-up will be done every 2 months and every 3 months in the second year. History taking, physical examination, radiology and histopathology examination, UEL index, and ICG lymphography evaluation will be done during follow-up. Each subject will complete the lymphedema quality of life questionnaire. The cumulative incidence of BCRL, the free survival time of BCRL, and SCL progression will be reported descriptively. BCRL risk factors and collateral lymphatic pathway will be observed as well.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative incidence of BCRL	BCRL definition: Post operation subject condition with presence of minimum DB 2 with one or both symptoms (swelling, heaviness), and increment of UEL index >10% compared to pre operation OR Post operation subject condition with presence of ≥ DB 2 with minimum area 30% in one arm region in one of the arm lymphatic pathway (anterior or posterior), without presence of symptoms (swelling or heaviness), and increment of UEL index >10% compared to pre operation	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BCRL and SCL progression-free survival rate	Percentage of subjects who do not progress to subclinical lymphedema or lymphedema during the research.	1 year
Collateral lymphatic pathway	The number of lymphatic pathways flow into the region: supraclavicular, internal mammary, and contralateral axillary and supraclavicular nodes based on the ICG lymphography.	1 year
Quality of life lymphedema	Assessment of lymphedema quality of life score after the surgery using the lymphedema quality of life score questionnaire that is self-reported by the subjects every 2 months and every 3 months in the second year. Calculation of the lymphedema quality of life score is the summation of the score from each question. The minimum score is 0 and the maximum score is 100. A higher score indicates lower lymphedema quality of life.	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association of body mass index (BMI) with BCRL	BMI was calculated by weight (kilograms) and height (centimeters). Categorized based on Asia Pacific classification are overweight (BMI ≥ 23 kg/m^2) and no overweight (BMI < 23 kg/m^2). Measured at one time point.	1 year
Association of number of axillary lymph nodes metastases with BCRL	The number of metastases lymph nodes and classified into >3 lymph nodes and ≤3 lymph nodes. Measured at one time point.	1 year
Association of number of taxane chemotherapy with BCRL	Taxane chemotherapy data from the subject's medical record and categorized into yes or no. Measured at one time point.	1 year
Association of regional lymph node radiation with BCRL	Regional lymph node radiation data from the subject's medical record and categorized into yes or no. Measured at one time point	1 year
Association of axillary fat weight with BCRL	Axillary fat weight in grams is taken at the time of surgery. Measured at one time point.	1 year

Collaborators and Investigators

• Sponsor: Dharmais National Cancer Center Hospital
• Investigators: Principal Investigator: Bayu Brahma, MD, Dharmais Hospital National Cancer Center, Indonesia

Publications and helpful links

General Publications

• Yamamoto T, Yamamoto N, Doi K, Oshima A, Yoshimatsu H, Todokoro T, Ogata F, Mihara M, Narushima M, Iida T, Koshima I. Indocyanine green-enhanced lymphography for upper extremity lymphedema: a novel severity staging system using dermal backflow patterns. Plast Reconstr Surg. 2011 Oct;128(4):941-947. doi: 10.1097/PRS.0b013e3182268cd9.
• Brahma B, Putri RI, Reuwpassa JO, Tuti Y, Alifian MF, Sofyan RF, Iskandar I, Yamamoto T. Lymphaticovenular Anastomosis in Breast Cancer Treatment-Related Lymphedema: A Short-Term Clinicopathological Analysis from Indonesia. J Reconstr Microsurg. 2021 Oct;37(8):643-654. doi: 10.1055/s-0041-1723940. Epub 2021 Mar 1.
• Brahma B, Yamamoto T. Breast cancer treatment-related lymphedema (BCRL): An overview of the literature and updates in microsurgery reconstructions. Eur J Surg Oncol. 2019 Jul;45(7):1138-1145. doi: 10.1016/j.ejso.2019.01.004. Epub 2019 Jan 4.
• Yamamoto T, Narushima M, Yoshimatsu H, Yamamoto N, Kikuchi K, Todokoro T, Iida T, Koshima I. Dynamic Indocyanine Green (ICG) lymphography for breast cancer-related arm lymphedema. Ann Plast Surg. 2014 Dec;73(6):706-9. doi: 10.1097/SAP.0b013e318285875f.
• Brahma B, Putri RI, Karsono R, Andinata B, Gautama W, Sari L, Haryono SJ. The predictive value of methylene blue dye as a single technique in breast cancer sentinel node biopsy: a study from Dharmais Cancer Hospital. World J Surg Oncol. 2017 Feb 7;15(1):41. doi: 10.1186/s12957-017-1113-8.
• Akita S, Nakamura R, Yamamoto N, Tokumoto H, Ishigaki T, Yamaji Y, Sasahara Y, Kubota Y, Mitsukawa N, Satoh K. Early Detection of Lymphatic Disorder and Treatment for Lymphedema following Breast Cancer. Plast Reconstr Surg. 2016 Aug;138(2):192e-202e. doi: 10.1097/PRS.0000000000002337.
• Ishiura R, Yamamoto T, Saito T, Mito D, Iida T. Comparison of Lymphovenous Shunt Methods in a Rat Model: Supermicrosurgical Lymphaticovenular Anastomosis versus Microsurgical Lymphaticovenous Implantation. Plast Reconstr Surg. 2017 Jun;139(6):1407-1413. doi: 10.1097/PRS.0000000000003354.
• Yamamoto T, Yamamoto N, Hara H, Mihara M, Narushima M, Koshima I. Upper extremity lymphedema index: a simple method for severity evaluation of upper extremity lymphedema. Ann Plast Surg. 2013 Jan;70(1):47-9. doi: 10.1097/SAP.0b013e3182275d23.
• Suami H. Anatomical Theories of the Pathophysiology of Cancer-Related Lymphoedema. Cancers (Basel). 2020 May 23;12(5):1338. doi: 10.3390/cancers12051338.

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2022
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): November 18, 2027

Study Registration Dates

• First Submitted: November 22, 2022
• First Submitted That Met QC Criteria: January 11, 2023
• First Posted (Actual): January 12, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 19, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Axillary Lymph Node Dissection; Lymphatic Bypass Supermicrosurgery; Primary Lymphedema Prevention
• Additional Relevant MeSH Terms: Postoperative Complications; Pathologic Processes; Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Lymphatic Diseases; Breast Cancer Lymphedema; Breast Neoplasms; Lymphedema
• Other Study ID Numbers: 227/KEPK/IX/2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All of the individual participant data collected during the trial will be shared. The researcher provides a methodologically sound proposal. The proposal should be directed to bbrahma@dharmais.co.id. To gain access, data requestors will need to sign a data access agreement.
• IPD Sharing Time Frame: Beginning 6 months and ending 3 years following article publication.
• IPD Sharing Access Criteria: Qualified researchers who have received principal investigator's approval.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No