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Randomized, double-blind comparison of indocyanine green with or without albumin premixing for near-infrared fluorescence imaging of sentinel lymph nodes in breast cancer patients

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Abstract

Near-infrared (NIR) fluorescence imaging has the potential to improve sentinel lymph node (SLN) mapping in breast cancer. Indocyanine green (ICG) is currently the only clinically available fluorophore that can be used for SLN mapping. Preclinically, ICG adsorbed to human serum albumin (ICG:HSA) improves its performance as a lymphatic tracer in some anatomical sites. The benefit of ICG:HSA for SLN mapping of breast cancer has not yet been assessed in a clinical trial. We performed a double-blind, randomized study to determine if ICG:HSA has advantages over ICG alone. The primary endpoint was the fluorescence brightness, defined as the signal-to-background ratio (SBR), of identified SLNs. Clinical trial subjects were 18 consecutive breast cancer patients scheduled to undergo SLN biopsy. All patients received standard of care using 99mTechnetium-nanocolloid and patent blue. Patients were randomly assigned to receive 1.6 ml of 500 μM ICG:HSA or ICG that was injected periareolarly directly after patent blue. The Mini-Fluorescence-Assisted Resection and Exploration (Mini-FLARE) imaging system was used for NIR fluorescence detection and quantitation. SLN mapping was successful in all patients. Patient, tumor, and treatment characteristics were equally distributed over the treatment groups. No significant difference was found in SBR between the ICG:HSA group and the ICG alone group (8.4 vs. 11.3, respectively, P = 0.18). In both groups, the average number of detected SLNs was 1.4 ± 0.5 SLNs per patient (P = 0.74). This study shows that there is no direct benefit of premixing ICG with HSA prior to injection for SLN mapping in breast cancer patients, thereby reducing the cost and complexity of the procedure. With these optimized parameters that eliminate the necessity of HSA, larger trials can now be performed to determine patient benefit.

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Acknowledgments

We thank the following individuals for the contribution to this study: Gemma Ranke, Elly Krol-Warmerdam, Annemarie Voet-van den Brink, Gerlinda van Gent-de Bruijn (Breast Cancer Unit) and Linda van der Hulst (Central Pharmacy). We thank Lindsey Gendall for editing. This work was supported in part by NIH grants R01-CA-115296 and R21-CA-130297, the Dutch Cancer Society grant UL2010-4732, the Nuts Ohra Fund, the “Maurits and Anna de Kock” Foundation and the American Women’s Club of The Hague. J.S.D. Mieog is a MD-medical research trainee funded by The Netherlands Organisation for Health Research and Development (grant nr. 92003526).

Conflict of Interest

Merlijn Hutteman, J. Sven D. Mieog, Joost R. van der Vorst, Gerrit-Jan Liefers, Hein Putter, Clemens W.G.M. Löwik, Cornelis J.H. van de Velde, Alexander L. Vahrmeijer have stated that they have no conflict of interest.

John V. Frangioni, M.D., Ph.D.: Mini-FLARE technology is owned by Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School. As inventor, Dr. Frangioni may someday receive royalties if products are commercialized. Dr. Frangioni is the founder and unpaid director of The FLARE Foundation, a non-profit organization focused on promoting the dissemination of medical imaging technology for research and clinical use.

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Authors and Affiliations

  1. Department of Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands

    Merlijn Hutteman, J. Sven D. Mieog, Joost R. van der Vorst, Gerrit Jan Liefers, Cornelis J. H. van de Velde & Alexander L. Vahrmeijer

  2. Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands

    Hein Putter

  3. Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

    Clemens W. G. M. Löwik

  4. Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA

    John V. Frangioni

  5. Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02215, USA

    Merlijn Hutteman & John V. Frangioni

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  1. Merlijn Hutteman
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  2. J. Sven D. Mieog
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  3. Joost R. van der Vorst
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  4. Gerrit Jan Liefers
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  5. Hein Putter
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  6. Clemens W. G. M. Löwik
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  7. John V. Frangioni
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  8. Cornelis J. H. van de Velde
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  9. Alexander L. Vahrmeijer
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Corresponding author

Correspondence to Alexander L. Vahrmeijer.

Additional information

Merlijn Hutteman and J. Sven D. Mieog contributed equally to the study and share first authorship.

Clinical Trial Registration: The Netherlands Trial Register NTR2482.

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Hutteman, M., Mieog, J.S.D., van der Vorst, J.R. et al. Randomized, double-blind comparison of indocyanine green with or without albumin premixing for near-infrared fluorescence imaging of sentinel lymph nodes in breast cancer patients. Breast Cancer Res Treat 127, 163–170 (2011). https://doi.org/10.1007/s10549-011-1419-0

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