Implementation of Indocyanine Green to Identify Sentinel Lymph Nodes During Surgery for Breast Cancer

NCT ID: NCT07146295

Last Updated: 2026-01-12

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

NA

Total Enrollment

1760 participants

Study Classification

INTERVENTIONAL

Study Start Date

2025-04-18

Study Completion Date

2026-08-31

Brief Summary

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The goal of this clinical trial is to learn how to successfully introduce a new method for finding the sentinel lymph node during breast cancer surgery into routine hospital care. The method uses a dye called indocyanine green (ICG) and a special camera to see the lymph node. The sentinel lymph node is the first lymph node that cancer is likely to spread to.

In the Netherlands, about 1 in 7 women develops breast cancer. Finding out whether cancer has spread to the lymph nodes is important for planning treatment and predicting outcomes. The current standard method for sentinel lymph node biopsy (SLNB) uses a radioactive tracer called radioisotope technetium-labeled (99mTc)-nanocolloid. While accurate, this method has several drawbacks: it exposes patients to radioactivity, requires an extra hospital visit or travel to another hospital due to limited nuclear medicine facilities, and is not sustainable. Surgeries using 99mTc can only take place on certain days due to logistical issues, and the signal from 99mTc can be disturbed by the tumor marker placed in the breast.

ICG works as well as 99mTc for SLNB and offers several advantages: it is given during surgery (no extra visit needed), produces no radiation, and reduces costs. However, it is still not widely used in the Netherlands because hospitals may not be familiar with it or unsure how to make the switch.

This study will introduce ICG step-by-step in several Dutch hospitals and evaluate how to make the change as smooth and effective as possible. It will take place in three stages: I) SLNB with 99mTc only (current practice); II) SLNB with both 99mTc and ICG (transition phase); III) SLNB with ICG only (full implementation).

All study procedures take place during planned surgery, with no extra hospital visits. After surgery, participants will receive a short questionnaire (10-15 minutes) to share their experiences with the procedure. Their feedback, combined with input from healthcare providers, will help researchers develop a uniform medical protocol, an implementation guide, and educational materials for surgeons and surgical trainees.

The aim is to make ICG widely available across the Netherlands, ensuring that care is less burdensome, more sustainable, and more cost-effective, while keeping treatment accessible in local hospitals.

Detailed Description

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Background:

Breast cancer affects one in seven women. Detecting lymph node metastases via the sentinel lymph node biopsy (SLNB) is crucial for prognosis and treatment. The gold standard is radio-guided surgery using the radioisotope technetium-labeled (99mTc)-nanocolloid, which requires preoperative injection and lymphoscintigraphy. However, the use of 99mTc poses significant burdens on patients, as it requires additional hospital visits or travel to another hospital due to the limited availability of nuclear medicine facilities. The use of 99mTc also creates logistical challenges and lacks sustainability. A recently proven, equally effective and safe alternative method is peroperative real-time fluorescence imaging using Indocyanine Green (ICG). ICG offers many advantages over 99mTc for patients, healthcare providers, and society. Yet, the use of ICG for SLNB remains limited, as hospitals face challenges due to uncertainty in transitioning and limited familiarity with recent findings. Implementation guidance is imperative for effective adoption, to avert further practice variation and to ensure patients benefit from this evidence-based alternative method.

Objectives:

The INFINITE trial aims to successfully implement ICG-fluorescence for identifying the sentinel lymph node by guiding the implementation process using the Effective Implementation of Change model developed by Grol and Wensing, identifying and understanding the factors influencing implementation outcomes through the Consolidated Framework for Implementation Research, evaluating the outcomes of implementation efforts using a mixed-methods approach and the outcomes framework proposed by Proctor et al., and creating conditions for nationwide implementation. Secondary aims are to develop a uniform medical protocol for the use of ICG for SLNB, to develop an implementation guide that aligns with current practice, to prepare educational materials for surgeons and modules for the curriculum of surgical residents (CASH), to produce patient information materials and organize interactive meetings for surgical healthcare providers and their teams, to further substantiate the effectiveness, safety, and cost-effectiveness of ICG, to increase support and a sense of urgency for ICG implementation by organizing informational sessions during annual conferences of the relevant scientific associations, and to facilitate nationwide scale-up by incorporating ICG into SLNB guidelines.

Study Design:

ICG will be implemented in seven strategically chosen Dutch hospitals during the INFINITE trial. These hospitals have been selected to represent different areas, settings, and sizes, ensuring broad applicability and support for subsequent nationwide implementation. The INFINITE trial is a multicenter hybrid effectiveness-implementation study using a stepped-wedge cluster trial design across three phases: Phase I, pre-implementation (99mTc only); Phase II, transition period (99mTc and ICG); and Phase III, post-implementation (ICG only). Based on site readiness and in consultation with the participating centers, three clusters will be formed, each consisting of two or three hospitals. Clusters will transition to the next phase at fixed intervals, creating an iterative learning cycle. This approach allows for regular evaluations of the implementation strategies, processes, and products, including the protocol, implementation guide, educational materials, and patient information. Process evaluations will inform adjustments using the ERIC-CFIR matching tool, ensuring rapid integration of lessons learned to enhance implementation in the next cluster.

Intervention:

In Phase I, pre-implementation, SLNB is performed using standard care with 99mTc injection and lymphoscintigraphy the day or morning before surgery, followed by radio-guided surgery with a gamma-detection probe. In Phase II, the transition period, SLNB is performed using both ICG and 99mTc. Patients receive 99mTc injection and lymphoscintigraphy before surgery, with the surgeon blinded to the imaging results. During surgery, after induction of general anesthesia and before axillary incision, 5 mg (2 ml) ICG is injected periareolarly, and SLNB is performed using fluorescence imaging. After excision of the sentinel lymph node(s), the standard gamma probe is used to test the excised nodes and the axilla for 99mTc activity, and the axilla is also explored by direct visualization and palpation. In Phase III, post-implementation, SLNB is performed using ICG as the sole tracer, with the same dosage and injection method, and the sentinel lymph node is visualized using fluorescence imaging and excised.

Outcomes:

Study endpoints are categorized into actual and anticipated implementation outcomes, client outcomes, and service outcomes. The primary endpoint is adoption, defined as the proportion of SLNB procedures conducted with ICG only, 99mTc only, or both during Phase III, compared to the total SLNBs in that phase, measured using screening logs and hospital records. All other outcomes are secondary. Fidelity, another actual implementation outcome, is measured through an intraoperative survey. Anticipated implementation outcomes such as appropriateness, feasibility, and acceptability are evaluated via a healthcare provider survey during Phase III. Client outcomes include patient satisfaction assessed through a post-procedure survey. Service outcomes encompass effectiveness, safety, cost-effectiveness, and the impact on necessary personnel, evaluated using perioperative and hospital administration data.

Risks and Burden:

Patients who consent will not experience any extra burden from ICG-fluorescence. ICG will be administered under general anesthesia, so patients will not experience additional discomfort, site visits, or procedures. ICG is non-ionizing and has very few reported complications or adverse events. Considering a maximum of two additional nodes sampled, the preferred anatomical location of these nodes, and the clinical experience with additional lymph node sampling, no increase in surgical morbidity is expected. Patients may benefit from the intervention as ICG can increase sentinel lymph node identification rates and eliminate the need for a preoperative visit to the Nuclear Medicine department for 99mTc injection. Completion of the patient satisfaction questionnaire will take approximately 10 to 15 minutes. Both risks and burden are therefore considered negligible.

Conditions

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Breast Cancer Sentinel Lymph Node Biopsy (SLNB) Sentinel Lymph Node Detection Sentinel Lymph Node Lymphatic Metastasis Fluorescence Imaging Indocyanine Green (ICG) Radioisotopes Lymph Node Mapping

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

SEQUENTIAL

This is a stepped-wedge cluster trial in which participating hospitals (clusters) are selected to represent different regions, settings, and sizes. The order in which hospitals transition is based on site readiness and in consultation with the participating centers. All hospitals begin with the current standard of care using radioisotope technetium-labeled (99mTc)-nanocolloid for sentinel lymph node biopsy (SLNB). At fixed intervals, clusters move to a transition phase using both 99mTc and indocyanine green (ICG), and then to ICG only. This sequential rollout creates an iterative learning cycle, allowing evaluation of the implementation process and refinements between phases. The total study duration is 18 months, with a fixed 6-month transition phase per cluster.
Primary Study Purpose

DIAGNOSTIC

Blinding Strategy

NONE

Study Groups

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Pre-implementation (99mTc only)

Participants undergo sentinel lymph node biopsy (SLNB) using the current standard of care: injection of radioisotope technetium-labeled (99mTc)-nanocolloid and preoperative lymphoscintigraphy, followed by radio-guided surgery with a gamma-detection probe.

Group Type ACTIVE_COMPARATOR

Technetium (99mTc)

Intervention Type DRUG

A radiopharmaceutical tracer consisting of technetium-99m (99mTc)-labelled nanocolloid used for sentinel lymph node mapping. In this study, 99mTc-nanocolloid is administered via periareolar injection with an activity of 40 MBq for the one-day protocol or 100 MBq for the two-day protocol, according to local hospital practice. Injection is performed either on the day of surgery or the afternoon before surgery. Preoperative lymphoscintigraphy is carried out to visualize lymphatic drainage. During surgery, a gamma-detection probe is used to locate and remove the sentinel lymph node(s) identified by 99mTc uptake.

Indocyanine Green

Intervention Type DRUG

Indocyanine Green (ICG) is a fluorescent dye used for intraoperative sentinel lymph node mapping. In this study, a total dose of 5 mg (2 mL) of ICG is administered via periareolar injection after induction of general anesthesia and prior to axillary incision. During surgery, near-infrared fluorescence imaging is used to visualize lymphatic drainage and identify the sentinel lymph node(s). The identified node(s) are surgically removed under fluorescence guidance. In the transition phase, fluorescence findings are cross-checked against 99mTc uptake to ensure accuracy and safety.

Sentinel lymph node biopsy

Intervention Type PROCEDURE

Sentinel lymph node biopsy (SLNB) is a surgical procedure used to identify and remove the first lymph node(s) that drain lymph from a tumor area. In this study, SLNB is performed through a small axillary incision after mapping the sentinel lymph node(s) using either radioisotope technetium-labeled (99mTc)-nanocolloid, indocyanine green (ICG) fluorescence imaging, or a combination of both. The identified lymph node(s) are excised and sent for pathological examination to determine the presence of cancer cells. The procedure is carried out under general anesthesia as part of breast cancer surgery.

Transition phase (99mTc + ICG)

Participants receive preoperative injection of radioisotope technetium-labeled (99mTc)-nanocolloid and preoperative lymphoscintigraphy (without marking the location on the skin). Surgeons are blinded to preoperative lymphoscintigraphy results. After induction of general anesthesia, indocyanine green (ICG) is injected periareolar. Surgery is primarily guided by ICG fluorescence imaging to identify and remove the sentinel lymph node(s). Excised lymph nodes are then checked for 99mTc activity using a gamma-detection probe as a control. This phase is designed to allow surgeons to gain experience with the ICG technique while maintaining safety through parallel use of the established 99mTc method.

Group Type EXPERIMENTAL

Indocyanine Green

Intervention Type DRUG

Indocyanine Green (ICG) is a fluorescent dye used for intraoperative sentinel lymph node mapping. In this study, a total dose of 5 mg (2 mL) of ICG is administered via periareolar injection after induction of general anesthesia and prior to axillary incision. During surgery, near-infrared fluorescence imaging is used to visualize lymphatic drainage and identify the sentinel lymph node(s). The identified node(s) are surgically removed under fluorescence guidance. In the transition phase, fluorescence findings are cross-checked against 99mTc uptake to ensure accuracy and safety.

Sentinel lymph node biopsy

Intervention Type PROCEDURE

Sentinel lymph node biopsy (SLNB) is a surgical procedure used to identify and remove the first lymph node(s) that drain lymph from a tumor area. In this study, SLNB is performed through a small axillary incision after mapping the sentinel lymph node(s) using either radioisotope technetium-labeled (99mTc)-nanocolloid, indocyanine green (ICG) fluorescence imaging, or a combination of both. The identified lymph node(s) are excised and sent for pathological examination to determine the presence of cancer cells. The procedure is carried out under general anesthesia as part of breast cancer surgery.

Post-implementation (ICG only)

Participants undergo SLNB using ICG only. ICG is injected periareolar after induction of general anesthesia and visualized intraoperatively with a fluorescence camera to guide excision of the sentinel lymph node(s).

Group Type ACTIVE_COMPARATOR

Technetium (99mTc)

Intervention Type DRUG

A radiopharmaceutical tracer consisting of technetium-99m (99mTc)-labelled nanocolloid used for sentinel lymph node mapping. In this study, 99mTc-nanocolloid is administered via periareolar injection with an activity of 40 MBq for the one-day protocol or 100 MBq for the two-day protocol, according to local hospital practice. Injection is performed either on the day of surgery or the afternoon before surgery. Preoperative lymphoscintigraphy is carried out to visualize lymphatic drainage. During surgery, a gamma-detection probe is used to locate and remove the sentinel lymph node(s) identified by 99mTc uptake.

Sentinel lymph node biopsy

Intervention Type PROCEDURE

Sentinel lymph node biopsy (SLNB) is a surgical procedure used to identify and remove the first lymph node(s) that drain lymph from a tumor area. In this study, SLNB is performed through a small axillary incision after mapping the sentinel lymph node(s) using either radioisotope technetium-labeled (99mTc)-nanocolloid, indocyanine green (ICG) fluorescence imaging, or a combination of both. The identified lymph node(s) are excised and sent for pathological examination to determine the presence of cancer cells. The procedure is carried out under general anesthesia as part of breast cancer surgery.

Interventions

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Technetium (99mTc)

A radiopharmaceutical tracer consisting of technetium-99m (99mTc)-labelled nanocolloid used for sentinel lymph node mapping. In this study, 99mTc-nanocolloid is administered via periareolar injection with an activity of 40 MBq for the one-day protocol or 100 MBq for the two-day protocol, according to local hospital practice. Injection is performed either on the day of surgery or the afternoon before surgery. Preoperative lymphoscintigraphy is carried out to visualize lymphatic drainage. During surgery, a gamma-detection probe is used to locate and remove the sentinel lymph node(s) identified by 99mTc uptake.

Intervention Type DRUG

Indocyanine Green

Indocyanine Green (ICG) is a fluorescent dye used for intraoperative sentinel lymph node mapping. In this study, a total dose of 5 mg (2 mL) of ICG is administered via periareolar injection after induction of general anesthesia and prior to axillary incision. During surgery, near-infrared fluorescence imaging is used to visualize lymphatic drainage and identify the sentinel lymph node(s). The identified node(s) are surgically removed under fluorescence guidance. In the transition phase, fluorescence findings are cross-checked against 99mTc uptake to ensure accuracy and safety.

Intervention Type DRUG

Sentinel lymph node biopsy

Sentinel lymph node biopsy (SLNB) is a surgical procedure used to identify and remove the first lymph node(s) that drain lymph from a tumor area. In this study, SLNB is performed through a small axillary incision after mapping the sentinel lymph node(s) using either radioisotope technetium-labeled (99mTc)-nanocolloid, indocyanine green (ICG) fluorescence imaging, or a combination of both. The identified lymph node(s) are excised and sent for pathological examination to determine the presence of cancer cells. The procedure is carried out under general anesthesia as part of breast cancer surgery.

Intervention Type PROCEDURE

Other Intervention Names

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99mTc Technetium-99m labelled nanocolloid Technetium-99 Technetium-99m Tc99 ICG fluorescence imaging Sentinel lymph node mapping SLNB SLN procedure Sentinel lymph node procedure

Eligibility Criteria

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Inclusion Criteria

* Patients ≥ 18 years old.
* DCIS or invasive breast cancer, confirmed by biopsy
* Clinically node-negative, confirmed by preoperative axillary ultrasound
* Indication for breast cancer surgery with SLN procedure via axillar incision

Exclusion Criteria

* Combined MARI procedure
* Known allergy for Indocyanine Green (ICG), intravenous contrast or iodine
* History of axillary lymph node dissection
* Hyperthyroidism or thyroid cancer
* Pregnancy or breast-feeding
* No written informed consent according to ICH/GCP and national regulations.
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Canisius-Wilhelmina Hospital

OTHER

Sponsor Role collaborator

Spaarne Gasthuis

OTHER

Sponsor Role collaborator

Noordwest Ziekenhuisgroep

OTHER

Sponsor Role collaborator

Alrijne Hospital

OTHER

Sponsor Role collaborator

Dijklander Ziekenhuis

OTHER

Sponsor Role collaborator

Ziekenhuisgroep Twente

OTHER

Sponsor Role collaborator

Diakonessenhuis, Utrecht

OTHER

Sponsor Role collaborator

ZonMw: The Netherlands Organisation for Health Research and Development

OTHER

Sponsor Role collaborator

Isabelle Henskens

OTHER

Sponsor Role lead

Responsible Party

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Isabelle Henskens

Coordinating investigator

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Annemiek Doeksen, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

St. Antonius Hospital

Locations

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Noordwest Ziekenhuisgroep

Alkmaar, , Netherlands

Site Status RECRUITING

Ziekenhuisgroep Twente

Hengelo, , Netherlands

Site Status RECRUITING

Spaarne Gasthuis

Hoofddorp, , Netherlands

Site Status RECRUITING

Dijklander Ziekenhuis

Hoorn, , Netherlands

Site Status RECRUITING

Alrijne Hospital

Leiden, , Netherlands

Site Status RECRUITING

Canisius Wilhelmina Ziekenhuis

Nijmegen, , Netherlands

Site Status RECRUITING

Diakonessenhuis

Utrecht, , Netherlands

Site Status RECRUITING

Countries

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Netherlands

Central Contacts

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Isabelle Henskens, MD

Role: CONTACT

+31883202902

Annemiek Doeksen, MD, PhD

Role: CONTACT

+3188 320 29 00.

Facility Contacts

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Gea Gooiker

Role: primary

+31725484160

Daniël Evers

Role: primary

+31887085232

Kirsten Blaauwendraat

Role: primary

+3123224 0000

Louise de Widt-Levert

Role: primary

+31299457457

Carmen van der Pol

Role: primary

+31715828987

Dominique van Uden

Role: primary

+3124-3658721

José Volders

Role: primary

+3188 250 5000

Other Identifiers

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10390172310041

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

NL87551.100.24

Identifier Type: -

Identifier Source: org_study_id

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