Finding Sentinel Lymph Nodes During Mastectomy Using Indocyanine Green (INIGMA Study) (INIGMA)

Indocyanine Green Guided Identification of Sentinel Lymph Nodes Via Mastectomy Incision in Breast Cancer Patients (INIGMA Study)

This pilot study evaluates the diagnostic value of indocyanine green (ICG) fluorescence for sentinel lymph node biopsy (SLNB) performed through the mastectomy incision in breast cancer patients.

Women with clinically node-negative, invasive T1-T3 breast cancer undergoing mastectomy with SLNB at St. Antonius or Isala Hospital will be included. All patients receive standard 99mTc injection preoperatively, followed by 5 mg (2mL) ICG injection after anesthesia. The axilla will be explored for fluorescent lymph nodes via the mastectomy incision, avoiding a separate axillary incision.

Primary outcome: ICG detection rate for SLN identification via the mastectomy incision.

Secondary outcomes: Comparison with 99mTc detection, number of nodes identified, concordance between methods, pathology differences, detection time, and complications.

ICG is safe, non-ionizing, and causes no extra discomfort or visits. Risks and burden are minimal.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Lymphatic Metastasis; Sentinel Lymph Node; Mastectomy; Radioisotopes; Lymph Node Mapping; Indocyanine Green (ICG); Sentinel Lymph Node Detection; Fluorescence Imaging; Sentinel Lymph Node Biopsy (SLNB)
• Intervention / Treatment: Other: Indocyanine green (ICG)-fluorescence guided sentinel lymph node biopsy

Detailed Description

Background:

Identifying lymphatic metastases is an important prognostic factor in the survival rate of breast cancer and the presence of lymphatic metastases carries consequences for further treatment. Results the non-inferiority INFLUENCE study and previous literature, led to the implementation of ICG-guided SLNBs via axillary incision as standard of care at the St. Antonius Hospital. The diagnostic performance of ICG-fluorescence for SNLBs using the mastectomy incision has not been described yet. Surgeons may perform SLNBs using the same incision as the mastectomy, rather than using an additional axillary incision. In such setting, extended operating distance and visualization with an improper angle might introduce challenges to identify the SLN by tracking lymphatic vessels into the axilla.

Objective:

This pilot study aims to identify the diagnostic value of indocyanine green (ICG) fluorescence imaging for SLNBs via the mastectomy incision.

Study design:

This is a multicenter, cross-sectional pilot study identifying the diagnostic value of indocyanine green (ICG) fluorescence imaging for SLN mapping via the mastectomy incision (different surgical approach).

Study population:

Women with breast cancer who are admitted to the St. Antonius Hospital or Isala Hospital. Inclusion criteria include clinically nodenegative, invasive T1-T3 breast cancer conformed by biopsy, preoperative axillary ultrasound to confirm clinical node-negative status and indication for mastectomy with SLN procedure.

Intervention:

All included patients will receive standard of care implying 99mTc injection the day before surgery. Consequently, 5 mg (2 ml) ICG will be injected periareolar after administration of general anaesthesia and before incision. The lateral edge of the standard mastectomy incision will be used to explore the axilla for ICG fluorescent lymph nodes to avoid a separate axillary incision. Then the excised nodes are tested for 99mTc activity with the standard gamma detecting probe as control. Lastly, the axilla will be explored with the standard gamma-probe for residual lymph nodes, and by common sight and palpation as a control.

Outcomes:

Primary: to assess the detection rate of the ICG method to identify the SLN via a mastectomy incision.

Secondary:

• The detection rate of 99mTc
• The difference in detection rate between ICG and 99mTc
• The median number of SLN identified with ICG and the standard 99mTc
• Percentage of SLNs that is fluorescent, but not positive for 99mTc
• Percentage of SLNs that are not fluorescent but positive for 99mTc
• The difference in pathology of the SLN found by ICG and 99mTc, including the difference between micro- and macro metastases (Mic and Mac resp.) and isolated tumor cells (ITCs)
• Detection time for the use of ICG to detect the SLN, defined as time between skin incision and SLN resection in minutes
• Complications, including wound infection, bleeding and lymphedema, of the combination of the ICG method and the standard 99mTc method to identify the SLN in mastectomies
• The number of serious adverse events from the combination of ICG and 99mTc

Risks and burden:

Consenting patients will not need to do anything extra than the standard of care outside signing the informed consent. Administration of ICG will be done while under general anaesthesia, so patients will not experience extra discomfort, neither do they need extra site visits as the follow-up will be done during the standard follow-up appointment. ICG is safe to use: it is nonionizing and knows little to no complications and adverse events. Considering the cut-off of 2 additional nodes, the preferable topographic location of these nodes and the clinical experience with additional lymph node sampling, no increase in risk of surgical morbidity is expected. Patients might benefit from the intervention as ICG can increase the identification rate of the sentinel lymph node procedure and might even replace 99mTc for SLN mapping. Thus, both risks and burden are minimal.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Isabelle Henskens, MD; Phone Number: +31883202902; Email: i.henskens@antoniusziekenhuis.nl
• Study Contact Backup: Name: Annemiek Doeksen, MD, PhD; Phone Number: +3183202900; Email: a.doeksen@antoniusziekenhuis.nl

Study Locations

• Netherlands
  • Overijssel
    • Zwolle, Overijssel, Netherlands, 8025 AB
      • Recruiting
      • Isala
      • Contact: Maarten Beek, MD, PhD; Phone Number: +3188 624 50 00; Email: m.a.beek@isala.nl
  • Utrecht
    • Utrecht, Utrecht, Netherlands, 3543 AZ
      • Recruiting
      • St. Antonius Ziekenhuis
      • Contact: Isabelle Henskens, MD; Phone Number: +31883202902; Email: i.henskens@antoniusziekenhuis.nl
      • Contact: Annemiek Doeksen, MD, PhD; Phone Number: +3183202900; Email: a.doeksen@antoniusziekenhuis.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinically node-negative, DCIS, invasive T1- T3 breast cancer confirmed by biopsy.
• Preoperative axillary ultrasound to confirm clinical node-negative status.
• Indication (or preference) for mastectomy and simultaneous SLN procedure.
• Written informed consent according to ICH/GCP and national regulations.

Exclusion Criteria:

• Patients < 18 years old
• Breast conserving surgery
• Direct reconstruction (with autologous tissue or implant)
• Known allergy for indocyanine green (ICG) or radioisotope technetium (99mTc), intravenous contrast or iodine
• Other concurrent solid tumour
• Hyperthyroidism or thyroid cancer
• Pregnancy or breast feeding
• Psychological, familial, sociological or geographical factors that could potentially hamper compliance with the study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ICG-fluorescence imaging with 99mTc control for SLNB; This experimental arm involves participants receiving indocyanine green (ICG) fluorescence imaging as the primary method for sentinel lymph node biopsy (SLNB), with 99mTc-nanocolloid serving as the within-patient control. Both methods are applied during the same surgical procedure. This design allows each participant to serve as their own control for comparing the diagnostic perfomance of both techniques directly in indentifying sentinel lymph nodes via mastectomy incision.

Other: Indocyanine green (ICG)-fluorescence guided sentinel lymph node biopsy; ICG-fluorescence is used as the primary tracer to identify SLNs during SLNB in breast cancer surgery. The standard 99mTc-nanocolloid method is used as a control to verify the sentinel lymph nodes identified by ICG. Surgeons are blinded to preoperative lymphoscintigraphy results. After general anesthesia, 5 mg (2 mL of 2.5 mg/mL solutio) of ICG is injected sub-/intracutaneous periareolarly. ICG-fluorescence is detected using near-infrared imaging. SLNB via mastectomy incision is performed. The most fluorescent lymph node is excised first, followed by (maximal 2) additional fluorescent nodes. The excised nodes are tested for 99mTc-activity using a gamma probe. The axilla is then checked with the gamma probe and and palpation for any remaining nodes, which are excised if their radiation count exceeds 10% of the hottest node. All excised lymph nodes are sent for pathological examination to determine the presence of cancer cells. After surgery, the lymphoscintigraphy results are announced.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification rate of sentinel lymph nodes using indocyanine green fluorescence	The identification rate is defined as the proportion of participants in whom at least one sentinel lymph node (SLN) is successfully identified using indocyanine green (ICG) fluorescence imaging via the mastectomy incision during surgery.	During the surgical procedure (from skin incision to completion of sentinel lymph node resection)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification rate of sentinel lymph nodes using 99mTc	The identification rate is defined as the proportion of participants in whom at least one sentinel lymph node is identified using the standard-of-care radioisotope technetium-99m (99mTc) during the same surgical procedure.	During the surgical procedure (from skin incision to completion of sentinel lymph node resection)
Difference in sentinel lymph node detection rate between ICG and 99mTc	The absolute difference in identification rates between indocyanine green (ICG) fluorescence imaging and technetium-99m (99mTc) for sentinel lymph node detection within the same participant.	During the surgical procedure (from skin incision to completion of sentinel lymph node resection)
Number of sentinel lymph nodes identified per participant by ICG and 99mTc	The total number of sentinel lymph nodes identified per participant using indocyanine green (ICG) fluorescence imaging and using technetium-99m (99mTc) during surgery.	During the surgical procedure (from skin incision to completion of sentinel lymph node resection)
Proportion of participants with fluorescent sentinel lymph nodes among those identified by 99mTc	The percentage of participants in whom sentinel lymph nodes identified by the standard-of-care technetium-99m (99mTc) are also fluorescent when assessed with indocyanine green (ICG).	During the surgical procedure (from skin incision to completion of sentinel lymph node resection)
Fluorescent sentinel lymph nodes not positive for 99mTc	The percentage of sentinel lymph nodes that demonstrate fluorescence with indocyanine green (ICG) but show no detectable activity on technetium-99m (99mTc) assessment.	During the surgical procedure (from skin incision to completion of sentinel lymph node resection)
Sentinel lymph nodes positive for 99mTc but not fluorescent	The percentage of sentinel lymph nodes that are positive for technetium-99m (99mTc) activity but do not demonstrate fluorescence with indocyanine green (ICG).	During the surgical procedure (from skin incision to completion of sentinel lymph node resection)
Pathological status of sentinel lymph nodes identified by ICG and 99mTc	Pathological assessment of sentinel lymph nodes identified by indocyanine green (ICG) and technetium-99m (99mTc), including the presence of isolated tumour cells, micrometastases, or macrometastases.	From surgical resection of sentinel lymph nodes until completion of histopathological assessment, assessed within approximately 3 weeks after surgery
Detection time for sentinel lymph node identification using ICG	Detection time is defined as the time in minutes between skin incision and resection of the first sentinel lymph node identified using indocyanine green (ICG) fluorescence imaging.	During the surgical procedure (from skin incision to sentinel lymph node resection)
Procedure-related complications associated with ICG and 99mTc	The proportion of participants experiencing complications related to the sentinel lymph node procedure using indocyanine green (ICG) and technetium-99m (99mTc), including seroma requiring drainage, wound infection requiring antibiotic or surgical treatment, bleeding requiring reoperation, and mild allergic reactions.	From surgery up to 2 months postoperatively
Serious adverse events related to ICG and 99mTc	The number of participants experiencing serious adverse events related to indocyanine green (ICG) or technetium-99m (99mTc), including severe allergic reactions, death, or other serious adverse events.	From surgery up to 2 months postoperatively

Collaborators and Investigators

• Sponsor: Isabelle Henskens
• Collaborators: Isala

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2022
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: January 9, 2026
• First Submitted That Met QC Criteria: January 15, 2026
• First Posted (Actual): January 23, 2026

Study Record Updates

• Last Update Posted (Actual): January 23, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Breast cancer; Mastectomy; Indocyanine green; Sentinel lymph node biopsy; Surgical oncology; Fluorescence imaging; Lymph node mapping; Radioisotope; Techetium nanocolloïd
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplastic Processes; Skin Diseases; Breast Diseases; Neoplasm Metastasis; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Breast Neoplasms; Lymphatic Metastasis; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indoles; Indocyanine Green
• Other Study ID Numbers: NL80591.100.22

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: At present, there is no final decision regarding sharing of individual participant data (IPD). Data sharing will depend on ethical approval, participant consent, and compliance with applicable privacy regulations. If IPD sharing is pursued, only de-identified datasets relevant to the research question will be made available upon reasonable request to qualified researchers, under a data use agreement ensuring confidentiality and scientific integrity

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No