A Dose-Image Optimization Trial for Voluven®-Assisted Indocyanine Green Fluorescence-Guided Breast Cancer Sentinel Lymph Node Surgery

Abstract

Background: Sentinel lymph node biopsy (SLNB) is critical in breast cancer staging, and indocyanine green (ICG) has emerged as a promising fluorescent tracer. Optimizing ICG concentration with an appropriate solvent such as Voluven® could improve imaging quality and SLN detection, yet the ideal protocol remains undefined. This study investigates the optimal ICG:Voluven concentration for SLNB in breast cancer surgery.

Patients and methods: In a prospective trial (April 2022-June 2023), 12 women with early breast cancer underwent SLNB with ICG:Voluven at 0.5 mg/mL (5×, n = 3), 0.25 mg/mL (10×, n = 6), or 0.125 mg/mL (20×, n = 3). Outcomes included SLN retrieval, signal-to-background ratio (SBR), areola-to-axilla traveling time (AAT), safety, and cost, assessed via Stryker SPY Portable Handheld Imaging System.

Results: The 10× group (0.25 mg/mL) showed the highest median SBR (127.4, range 90.9-256.0) versus 5× (26.3, 2.7-133.2) and 20× (39.1, 5.3-98.4), retrieving three SLNs per patient consistently, unlike fewer in other groups. The 20× group had the shortest AAT (44.3 s) but lower SBR and procedural issues (e.g., subcutaneous dissection). The 5× group had the longest AAT (144.3 s) and reduced SLN detection. No adverse events occurred. The equivalent drug cost was around 1.5 US dollars per patient.

Conclusions: The 0.25 mg/mL ICG:Voluven concentration offers an optimal balance of fluorescence imaging quality, SLN detection, and procedural efficiency for SLNB in breast cancer surgery. Its safety, effectiveness, and low cost make it a practical choice, especially in resource-limited settings. Larger studies are needed to validate these results and refine the protocol further.

Keywords: 6% hydroxyethyl starch; Breast cancer; Dose optimization; Fluorescence-guided surgery; Indocyanine green; Sentinel lymph node biopsy.

Fig. 1.

The diagram of study design and patient grouping; the first part of the study compared using water and Voluven® as solvent, while the second part of the study tested different dilution ratio for best fluorescence imaging; the “more diluted” groups and the “more concentrated” groups were cancelled due to inferior results of the 20× dilution group and 5× dilution group

Fig. 2

Three-way connector technique was used to prepare different concentrations of the ICG:Voluven solution; Voluven® (10 mL) was used to dissolve powdered ICG instead of stock distilled water; the reconstituted ICG:Voluven solution (2.5 mg/mL) was withdrawn from the vial and transferred into a 5 mL syringe via the connector; a calculated volume of diluent Voluven® solution was then added, for example, to achieve a 10× dilution, 0.5 mL of ICG:Voluven (2.5 mg/mL) was combined with 4.5 mL of Voluven®; this technique minimizes contamination by preventing spreading or direct manual contact with the contrast agent

Fig. 3

A AATs and injection volumes under different concentrations of ICG:Voluven; B signal-to-background ratios of the sequential SLNs; SBRs of the overexposed LNs were plotted as 256:1, while that of the undetected LNs were plotted as 1:1 (no contrast) for better visualization

Fig. 4

Example fluorescence images of the subcutaneous lymphatics of the breasts from different concentration groups; A a 59-year-old woman in the 5× concentration group showed uneven distribution of the fluorescence, which indicates incomplete emulsification and quenching of the ICG particles; B a 51-year-old woman in the 10× concentration group showed even subareolar fluorescence with thicker subcutaneous lymphatics, which could be a volume expansion effect of Voluven®; C a 43-year-old woman in the 20× concentration group showed great volume expansion effect of the lymphatics, but subcutaneous dissection effect around the injection site