The efficacy and safety of indocyanine green-hyaluronic acid mixture (LuminoMark™) for localization in patients with non-palpable breast lesions: a multi-center open-label parallel phase-2 clinical trial

Abstract

Background Increasing rates of breast cancer screening have been associated with an increasing frequency of non-palpable breast lesions detection. Preoperative breast lesion localization is essential for optimizing excision accuracy. This study aimed to evaluate the efficacy and safety of indocyanine green (ICG) hyaluronic acid injection as a novel mixture for localization. Methods We performed a prospective clinical trial with female patients who underwent surgery for non-palpable breast lesions. All patients were sequentially assigned to the control group (localization with activated charcoal), Test Group 1 (ICG-hyaluronic acid mixture 0.1 mL), or Test Group 2 (ICG-hyaluronic acid mixture 0.2 mL) by 1:1:1 ratio. Results A total of 44 patients were eligible for this study (Control Group = 14, Test Group 1 = 15, Test Group 2 = 15 patients). Fibroadenoma (n = 17, 38.6%) accounted for the largest proportion of diagnoses, and five patients (11.4%) were diagnosed with malignancies. There were no statistically significant differences in baseline characteristics among the three groups. The marking rate was over 86% in all groups, with no significant intergroup differences. Skin pigmentation was only observed in the control group. The mean accuracy of resection (the greatest diameter of the excised specimen divided by the greatest diameter of the preoperative lesion as observed using ultrasonography, with values closer to 1 reflecting a higher accuracy) was 3.7 in the control group, 2.2 in Test Group 1, and 2.1 in Test Group 2 (p = 0.037 between Controls and Test Group 1, p = 0.744 between Test Group 1 and Test Group 2, and p = 0.026 between Controls and Test Group 2). Conclusion ICG-hyaluronic acid injection is a novel method that was shown to accurately localize non-palpable breast lesions and was associated with no skin pigmentation. Further research is required to apply this method to malignant breast lesions. Trial registration “A Multicenter Open-label, Parallel, Phase 2 Clinical Trial to Evaluate the Efficacy and Safety of LuminoMark™ Inj. (Conc. for Fluorescence) Localization in Patients with Non-palpable Breast Lesions” was prospectively registered as a trial (ClinicalTrials. gov Identifier: NCT03743259, date of registration: May 29, 2018, https://clinicaltrials.gov/ct2/show/NCT03743259)

The efficacy and safety of an indocyanine green−hyaluronic acid mixture (LuminoMark™) for localization in patients with non-palpable breast lesions: A multicenter, randomized, open-label, parallel phase 3 clinical trial

“…Similarly, in the phase 2 clinical trial, the accuracy of resection defined as the maximum diameter of the resected specimen divided by the maximum diameter of the preoperative lesion detected in the US was evaluated and the control group was found to have a higher value than the study group. The reason for the wider resection in the control group was because the injection amount of activated charcoal was higher than that of the ICG-HA (18). On the contrary, histopathological accuracy was higher in the control group than that in the study group, although the injection amount of activated charcoal was not reduced in this phase 3 clinical study.…”

“…However, the sample size was small (n = 44). In addition, only breast benign diseases were included (18). In this study, we evaluated the efficacy and safety of ICG-HA for localizing nonpalpable breast lesions including breast cancer with a larger sample size (n = 108).…”

“…= 47:53 ≈ 48 1) Level of significance, a= 0.025 (one-sided) 2) Power of the test, 1-b= 0.8 3) Allocation ratio= 1:1 4) Resection margin negative rate; study group, p t 0.811 5) Resection margin negative rate; control group, p c 0.811 6) Limit of non-inferiority, -d= -0.225 In this clinical trial, 0.2 mL of ICG-HA mixture (LuminoMark ™ , Hanlim Pharm. Co., Ltd., Korea) injection was set as the dose of the test drug, and 0.3 -1 mL of activated charcoal (Chacotrace ® , Phebra, Australia) was set as the control according to the results of the phase 2 clinical trial (18).…”

“…However, there is no report of tattooing localization using ICG under US-guidance for non-palpable breast lesions. Through a phase-2 clinical trial, we have suggested that ICG-hyaluronic acid (HA) (LuminoMark ™ ) can be used for accurate preoperative localization without skin pigmentation in benign breast diseases (18). The aim of this study was to evaluate the efficacy and safety of ICG-HA for localizing non-palpable breast lesions including breast cancer and confirm that ICG-HA is not inferior to activated charcoal, which has been widely used.…”

Efficacy of indocyanine green fluorescence for the identification of non-palpable breast tumours: systematic review

“… 23 , breast tumours positively identified using intraoperative molecular imaging in situ ; Kim et al . 24 , percentage of patients identified with localized target lesions for surgery; Lee et al . 17 , not reported; Liu et al .…”