The Efficacy and Safety of Indocyanine green- hyaluronic acid mixture (LuminoMarkTM) for Localization in Patients with Non-palpable Breast Lesions: A Multi-center Open-label Parallel Phase-2 Clinical trial

doi:10.21203/rs.3.rs-24969/v3

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The Efficacy and Safety of Indocyanine green- hyaluronic acid mixture (LuminoMarkTM) for Localization in Patients with Non-palpable Breast Lesions: A Multi-center Open-label Parallel Phase-2 Clinical trial

https://doi.org/10.21203/rs.3.rs-24969/v3

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published 16 Mar, 2021

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Backgrounds With increasing screening for breast cancer, non-palpable breast lesions are detected more frequently. A preoperative localization is very important for a minimal but accurate excision of a non-palpable breast lesion. The purpose of this study was to evaluate the efficacy and safety of indocyanine green(ICG)-hyaluronic acid mixture injection as a novel material for localization.

Methods We performed prospective clinical trial with female patients who underwent surgery for non-palpable breast lesion. All patients were sequentially assigned to the control group(localization with activated charcoal), test group 1(ICG-hyaluronic acid mixture 0.1ml), or test group 2(ICG-hyaluronic acid mixture 0.2ml) by 1:1:1 ratio.

Results A total of 44 patients were eligible for this study (control group = 14, test 1 group = 15, test 2 group = 15 patients ). Among all patients, Fibroadenoma accounted for the largest share (38.6%, 17/44) and malignancy accounted for 11.4% (5/44). There was no difference in baseline characteristics in three groups. The marking rate was over 86% in all groups, and there was no difference. However, skin pigmentation was only in the control group and the accuracy of resection (the greatest length in cm of the excised specimen divided by the greatest length in cm on the pre-operation ultrasound image, the value closer to 1 meant resection as much as the size on ultrasound image) was different significantly. The average was 3.7 in control group and 2.2 in test 1 group and 2.1 in test 2 group. ( p-value was 0.037 between control and test 1 group, 0.744 between test 1 and test 2 group, 0.026 between control and test2 group respectively. )

Conclusion ICG-hyaluronic acid mixture injection is a new method for localization with non-palpable breast lesions, as well as a better method with higher accuracy of resection, lower skin pigmentation. Further research is required to apply this method to malignant breast lesions.

Trial registration “A Multi-center Open-label Parallel Phase-2 Clinical trial to evaluate the efficacy and safety of LuminoMark^TM for 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).

General Surgery

Oncology

Breast

Localization

Indocyanine green

With increasing screening for breast cancer, non-palpable breast lesions are detected more frequently. (1) Image-guided localization has been shown to decrease positive margin rates and result in fewer re-excisions. (2)

In general, there were several ways for localization of non-palpable breast lesions. For example, skin marking with pen, wire, and tattoo localization. Skin marking with a pen under ultrasound(US) guidance is easy, but it can be easily erased and affected by patients’ movements. (3) Wire localization was the standard technique in the early 2000s, but had several disadvantages; patients discomfort, wire migration, and interference with surgical approaches. (4) US guided tattooing localization is an accurate and safe method; however, skin pigmentation is common. (5)

A preoperative localization is very important for a minimal but accurate excision of a non-palpable breast lesion. The ICG-hyaluronic acid mixture (LuminoMark^TM) is a material for accurate preoperative localization but no pigmentation. The purpose of this study was to evaluate the efficacy and safety of ICG-hyaluronic acid mixture injection as a novel material for localization.

In this prospective, multi-center open-label parallel clinical trial (ClinicalTrials. gov Identifier: NCT03743259), we included 50 female patients with non-palpable breast lesions who then underwent surgery at Samsung Medical Center and Myongi Hospital between January 2018 and March 2019. This study was approved by the Institutional Review Board of Samsung Medical Center ( IRB No. 2017-10-094 ) and Myongi Hospital ( IRB No. 2018-08-005 ). All patients provided written informed consent.

Study Design

The remaining 44 patients were sequentially assigned to the control group, test group 1, or test group 2 by 1:1:1 ratio (Figure 1). Figure 2 shows the flow for trial. Screening was done from three to 42 days before surgery. All patients had a history taken, physical examination, chest x-ray, endocardiogram (EKG), mammography (MMG), ultrasound (US) for breasts, and urine human chorionic gonadotropin (hCG). A day or an hour before surgery, localization was done by four dedicated radiologists through US guidance. For localization, 0.3 to 1.0 ml activated charcoal(Charcotrace^TM,40 mg/ml) was injected through an 18-gauge needle in the control group. Then 0.1 ml ICG-hyaluronic acid mixture was injected in test group 1 and 0.2 ml was injected in test group 2 through 21-gauge needles. The optimal injection dosage was decided on by means of s pretest with each material. The ICG-hyaluronic acid mixture was in the form of a solution mixed with indocyanine green 0.01 mg and hyaluronic acid 4 mg/2 ml. Localization with activated charcoal was seen by naked eye. Localization with ICG-hyaluronic acid mixture was seen in near-infrared fluorescence. Surgery was done by five breast surgeons. During the surgery, we took photos before the skin incision, after the skin incision, and after excision (Figures 3 and 4). A day after surgery, a post-operation check was done, and the last follow up with a photo was at 7-17 days after surgery.

Variables for evaluation

The primary objective of this trial is to evaluate the safety of use of ICG-hyaluronic acid mixture. We defined all the harmful reactions that occurred after injection or surgery as adverse events (AE). The primary endpoint was the accuracy of resection, which was defined as the value of the largest length (cm) of the excised specimen divided by the greatest length (cm) on pre-OP US.

Secondary endpoints were the success rate of marking on the breast lesion, marking on the excised specimen, the pathological accuracy, and the pigmentation on the skin. The rate of marking on the breast lesion as defined as percentage of patients identified as localization of target lesion for surgery. The rate for marking on the excised specimen as defined as percentage of patients identified as staining of excised specimen. The pathological accuracy was defined as the value of the largest length (cm) of the pathological lesion divided by the greatest length (cm) of the excised specimen. The pigmentation on the skin was defined as the case where pigment remains on the skin after surgery.

Inclusion Criteria

Patients who had a non-palpable breast lesion that could be identified by breast US, were over 19 or under 80 years of age, had agreed to participate in the trial.

Exclusion Criteria

Patients who had a palpable breast lesion, were under 19 or over 80 years of age, were pregnant, had a skin disease (scleroderma, systemic lupus erythematous), had a history of radiotherapy, neoadjuvant therapy, inflammatory breast cancer, or and drug (charcoal, indocyanine green, hyaluronic acid) allergy were excluded. Among 50 patients with consent, six were excluded because of withdrawal of consent, cancellation of surgery, or and screening out.

Statistical Analysis

The data in this study were examined for differences using the chi-square test or Fisher’s exact test. Differences in mean value were assessed using the Mann-Whitney test. We used SPSS software version 19. 0 (SPSS, IBM Corp, Amonk, USA). P values < 0. 05 were considered to be statistically significant.

A total of 44 patients were eligible for this study. Control group was 14 patients and test 1,2 group was 15 patients for each. Table 1 shows the baseline characteristics of the included patients. Most were over 40 years old, and there were no differences of age distribution or average age in three groups. According to the pathologic results, fibroadenoma accounted for the largest share (38.6%, 17/44) and malignancy accounted for 11.4% (5/44). Others included fibrocystic change, inflammation, and fat necrosis. The greatest lengths of preoperative US (pre-OP-US) were mostly under 2 cm, there was no difference between three groups. The longest excised specimens were mostly between 2 and 3 cm, and there was no difference between three groups. The longest one was 8 cm in the control group; it was diagnosed as malignancy.

Table 2 shows the accuracy of resection in all patients as the primary end point. The average in the control group was 3.7 and ranged from 1.2 to 13. 3. The average in test group 1 was 2.2 and ranged from 1.0 to 4.2. The average in test group 2 was 2.1 and ranged from 1.0 to 4.2. The average was the highest in the control group and was statistically different from that of the test groups. Analysis showed p = 0. 037 between the control group and test group 1, p = 0. 026 between the control group and test group 2, and p = 0.744 between the test groups.

Table 3 shows variables for secondary end points and adverse events in each group. The marking rate on both breast lesions and excised specimens was over 86% in all groups, and there was no difference. However, skin pigmentation was only in the control group (9/14, 64. 8%), and the difference was statistically significant. The pathological accuracy was measured by a dedicated pathologist. There were nine cases in which measurement was impossible (9/44, 20. 4%); there was fibrocystic change in three cases, inflammation in one case, intraductal papilloma in two cases, and atypical ductal hyperplasia in one case. Except for the nine impossible cases, the pathological accuracy could be calculated. The average in the control group was 0.3 and ranged from 0.1 to 0.9. The average in test group 1 was 0.4 and ranged from 0.2 to 0.8. The average in test group 2 was 0.4 and ranged from 0.2 to 0.9. Analysis showed that p = 0. 331 between the control group and test group 1, p = 0. 914 between the control group and test group 2, and p = 0. 389 between the test groups. There was no significant difference between the three groups. As previously known, side effects of ICG could be nausea, urticaria and fever in rare case especially in the patient with iodine hypersensitivity. However, there was no AE in all patients.

In this prospective study, we evaluated the efficacy and safety of ICG-hyaluronic acid mixture as novel material for localization. There was no AE in any of the groups. There was no significant difference in the pathological accuracy, marking rate on breast lesions, or excised specimens. However, there were significant differences in the accuracy of resection and skin pigmentation.

The resected size during the surgery for non-palpable lesion with localization could be larger than the resected size during the surgery for palpable lesion. The accuracy of resection (the greatest length in cm of the excised specimen divided by the greatest length in cm on the pre-OP US) reflects the ratio for over excision. The value closer to 1 meant resection as much as the size on pre OP US and also resection without useless tissue. The mean of this value was 3.7 in control group, which was higher than the value in test group 1 or test group 2 (p = 0. 037 and 0. 026 , respectively). It was because the injection dose of activated charcoal (0.3 to 1.0 ml) was much more than that of the ICG-hyaluronic acid mixture (0. 1 ml or 0. 2 ml). If activated charcoal had used the same dosage as ICG-hyaluronic acid mixture, it would have been an accurate comparison. However, if ICG-hyaluronic acid mixture 0.3 to 1.0 ml had been used, localization would have been impossible because of the spread with blur. Since a smaller resection could mean a better cosmetic result, the lower value of the accuracy of resection in the test groups than in the control group could mean a better cosmetic advantage for patients.

In addition, there was no difference between test group 1 using ICG-hyaluronic acid mixture 0. 1 ml and test group 2 using 0. 2 ml (p = 0. 744). Further, there was no difference in the marking rate on breast lesions and excised specimens between the test groups. For localization, ICG-hyaluronic acid mixture could be used with a dosage of either 0.1 ml or 0.2 ml.

The pathological accuracy (the greatest length of the pathological lesion in cm divided by the greatest length in cm of the excised specimen) is a unique variable in our study. The value closer to 1 means that resection was done for the actual pathological lesion. There were nine cases which were impossible to measure the pathological lesion among all the groups; hence this variable was insufficient to assess efficacy.

The greatest lengths on the pre OP-US were mostly under 2 cm, but the longest case was the 8 cm one in the control group that was diagnosed as a malignancy. The length of the excised specimen depended on the histological result, not on the differences in the three groups, which reflects the tendency to place a larger margin in malignant surgery than in benign surgery. If we analyzed only for malignancy cases, we would obtain more accurate results, but it was impossible with so few patients. Our patients group was heterogenous because only benign patients were included in the study, but hidden malignancy was discovered after surgery. In the future, we are planning a phase III clinical trial to evaluate positive margin rate in cancer patients.

In previous studies, tattooing had been used for various medical purposes (6). For example, US-guided charcoal tattooing for thyroid cancer was safe, easy, and well-tolerated for localization of non-palpable lesions in previously operated necks, with a high rate of success (7). For colorectal surgery, preoperative endoscopic tattooing was a safe and highly effective method for localization (8). The use of charcoal for breast marking has been demonstrated to be safe but pigmented in many studies (9-11). There was no study showing pigmentation rates and relevance to dosage. In our study, skin pigmentation occurred in 64.3% of the control group but in none of the test groups. The tattoo with charcoal could be removed when the cutting includes the site of skin (12), but it was impossible in excisions with small lesions. To avoid pigmentation, localization with ICG-hyaluronic acid mixture could be considered.

In previous studies, indocyanine green, which was the main material for ICG-hyaluronic acid mixture, was already used for medical purposes. For example, the indocyanine green retention rate at 15 min (ICGR15) is a useful marker of liver function in deciding on the extent of hepatectomy (13). In addition, Mok et al. reported that Indocyanine green encapsulated hyaluronic acid nanogels were used for highly selective detection of specific cancers and lymph nodes (14).

Meanwhile, we presented a new use for ICG-hyaluronic acid mixture. As previously described, ICG-hyaluronic acid mixture had advantages over activated charcoal in that there was no skin pigmentation and less pain, because of using smaller needle(21-gauge versus 18-gauge). However, it had a disadvantage in that it could be visualized only through a near-infrared fluorescence. so additional equipment was needed.

This study had several limitations. First, we did not enroll a large population, and there was no long-term follow up. Second, we used only length (cm) without volume (cm³or ml) which better reflects resection margin (15). Third, error from individual differences could have occurred, in that four radiologists, five surgeons, and three pathologists participated in localization, surgery, and pathological reading, respectively. Even with these limitations, this study is meaningful, because it had a prospective design and because there had been no research conducted regarding ICG-hyaluronic acid mixture for breast localization.

This is a multicenter phase-2 clinical trial to evaluate the efficacy and safety of ICG-hyaluronic acid mixture for localization compared to that activated charcoal. ICG-hyaluronic acid mixture injection was new method for localization and useful to obtain the accuracy of resection as well as cosmetic advantage. Further research is required for the method to be widely used. We have studied a small number of breast benign lesion patients, but we need to study a large number of malignant lesion patients to check the identification rate and pathological positive margin rate of new method compared to other localization methods. Further study about adverse events or survival rate after long-term follow up should be considered. In the future, we are planning a phase III clinical trial to evaluate positive margin rate in cancer patients.

ICG: indocyanine green ; US : ultrasound ; EKG : endocardiogram ; MMG ; mammography ; hCG : human chorionic gonadotropin ; Exam : examinatoin ; AE : adverse events ; pre-OP : preoperative ; ICGR15 : the indocyanine green retention rate at 15 min

Ethics approval and consent to participate

We declare that this study has obtained the report of ethics board approval and informed consent obtained from each participate has been written before surgery. The study was approved by the ethics committee of Samsung Medical Center ( IRB No. 2017-10-094 ) and Myongi Hospital ( IRB No. 2018-08-005 ).

Consent for publication

All participants gave a written consent for their personal and clinical details.

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was sponsored by Hanlim Pharm. Co., Ltd., a Korean pharmaceutical company dedicated to develop new medicine. They covered the cost of collecting data and stationers required. The funder has no role in analysis, interpretation and writing the manuscript.

Authors’ contributions

SWK, as a corresponding author, substantially contributed to the article as the conception and design of the work and manuscript revision. IK, as the first author, substantially contributed to the article as literature research, case collection and writing the manuscript. HJC, JMR, SKL, JHY, JEL, SJN and HJS were a contributors in case collection and interpretation of data. All authors read and approved the final manuscript.

Acknowledgements

This study was presented by poster at the 5^th World Congress on Controversies in Breast Cancer(CoBrCa) 2019.

Authors’ information

¹Department of Surgery, Bundang CHA Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu,Seongnam-si,Gyeonggi, Republic of Korea

²Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Republic of Korea

³ Department of Surgery, Myongji Hospital, Hanyang University College of Medicine, Gyeonggi, Republic of Korea

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Table 1 Baseline Characteristics of included Patients (total 44 patients )

		Control group (n = 14)	Test group 1 (n = 15)	Test group 2 (n = 15)	p-value
Age(yr)	<30	0 (0.0%)	0 (0.0%)	3 (20.0%)	0.143
	30≤ <40	1 (7.1%)	2 (13.3%)	1 (6.7%)
	40≤ <50	5 (35.7%)	9 (60.0%)	7 (46.7%)
	50≤	8 (57.1%)	4 (26.7%)	4 (26.7%)
	mean(range,yr)	52.2(39-68)	47.4(37-57)	442.(26-76)	0.112
Pathology	Fibroadenoma	4 (28.6%)	6 (40.0%)	7 (46.7%)	0.384
	Phyllodes tumor	0 (0.0%)	1 (6.7%)	1 (6.7%)
	Atypical ductal hyperplasia	4 (28.6%)	0 (0.0%)	0 (0.0%)
	Intraductal papilloma	2 (14.3%)	3 (20.0%)	4 (26.7%)
	Malignancy	1 (7.1%)	2 (13.3%)	2 (13.2%)
	Others	3 (21.4%)	3 (20.0%)	1 (6.7%)
the longest length on pre OP-US (cm)	<1	8 (57.1%)	5 (33.3%)	7 (46.7%)	0.500
	1≤ <2	5 (35.7%)	9 (60.0%)	6 (40.0%)
	2≤	1 (7.1%)	1 (6.7%)	2 (13.3%)
	mean(range,cm)	1.0(0.4-2.7)	1.2(0.6-2.8)	1.3(0.6-2.7)	0.379
the longest length of excised specimen (cm)	<1	0 (0.0%)	1 (6.7%)	1 (6.7%)	0.253
	1≤ <2	1 (7.1%)	3 (20.0%)	2 (13.3%)
	2≤ <3	6 (42.9%)	7 (46.7%)	7 (46.7%)
	3≤ <4	5 (35.7%)	1 (6.7%)	4 (26.7%)
	4≤	2 (14.3%)	3 (20.0%)	1 (6.7%)
	mean(range,cm)	3.0(1.5-8.0)	2.4(0.8-4.0)	2.5(0.6-6.2)	0.247

yr., year ; OP, operation; US, ultra sound

Table 2 Accuracy of Resection (The primary end point) in all patients

			the longest length of excised specimen (cm)		the longest length on pre OP-US (cm)	the accuracy of resection (cm/cm)	Mean (±sd)		p-value
Patients No.	Control group (n = 14)	1	3	1.4		2.1	3.7(±1.5)	0.037 (group1-2)
		2	3	0.7		4.3
		3	2.3	1.6		1.4
		4	3	0.8		3.8
		5	2	0.4		5
		6	1.5	0.6		2.5
		7	3.3	2.7		1.2
		8	8	0.6		13.3
		9	2	0.6		3.3
		10	2.5	0.8		3.1
		11	3	1		3
		12	2.8	1.4		2
		13	2	1		2
		14	4	0.9		4.4
	Test group 1 (n = 15)	1	2.5	1.3		1.9	2.2(±0.5)	0.744 (group2-3)
		2	2.5	1.4		1.8
		3	2	1.6		1.3
		4	1.2	0.7		1.7
		5	3.5	2.8		1.3
		6	1.5	1.1		1.4
		7	2	0.9		2.2
		8	2.4	0.8		3
		9	2.5	0.6		4.2
		10	2.5	1.4		1.8
		11	4	1.7		2.4
		12	1.3	1.3		1
		13	4	1.2		3.3
		14	0.8	0.6		1.3
		15	4	1		4
	Test group 2 (n = 15)	1	2	1.4		1.4	2.1(±0.5)	0.026 (group1-3)
		2	6.2	2		3.1
		3	1.2	0.6		2
		4	0.6	0.6		1
		5	2.2	1.7		1.3
		6	1	0.9		1.1
		7	3	0.8		3.8
		8	2.5	1.1		2.3
		9	2.5	0.6		4.2
		10	2.7	1.8		1.5
		11	3.5	2.7		1.3
		12	2.1	1.2		1.8
		13	2.8	0.8		3.5
		14	3.5	1.8		1.9
		15	1.1	0.9		1.2

No., numbers; OP, operation; US, ultra sound; sd, standard deviation

Table 3 Variables for Secondary End Points and Adverse Events in each Group

		Control group (n = 14)	Test group 1 (n = 15)	Test group 2 (n = 15)	p-value
Marking on breast lesion	Yes	13 (92.9%)	13 (86.7%)	14 (93.3%)	0.954
	No	1 (7.1%)	2 (13.3%)	1 (6.7%)
Marking on Excised specimen	Yes	13 (92.9%)	14 (93.3%)	15 (100.0%)	0.357
	No	1 (7.1%)	1 (6.7%)	0 (0.0%)
Skin Pigmentation	Yes	9 (64.3%)	0 (0.0%)	0 (0.0%)	0.000
	No	4 (28.6%)	15 (100.0%)	15 (100.0%)
	unknown	1 (7.1%)	0 (0.0%)	0 (0.0%)
The pathological accuracy	mean (±sd)	0.3 (±0.1)	0.4 (±0.1)	0.4 (±0.1)	0.331(group1-2) 0.389(group2-3) 0.914(group1-3)
Adverse Event(AE)	Yes	0(0.0%)	0(0.0%)	0(0.0%)	1.000
	No	14(100.0%)	15(100.0%)	15(100.0%)
sd, standard deviation

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The Efficacy and Safety of Indocyanine green- hyaluronic acid mixture (LuminoMarkTM) for Localization in Patients with Non-palpable Breast Lesions: A Multi-center Open-label Parallel Phase-2 Clinical trial

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