Abstract
Current standard of care localization techniques used in breast conserving surgery (BCS) after neoadjuvant chemotherapy (NACT) are expensive and may not be available in LMICs (lower-middle income countries). This review evaluated the efficacy of radio-opaque low-cost tumor markers. A systematic search was conducted as per PRISMA guidelines through November 30, 2022, for all studies using non-commercial radio-opaque tumor markers for patients undergoing BCS post NACT. Rate of unsatisfactory margin on final histology was the primary outcome. Oxford Centre for Evidence Based Medicine (OCEBM) levels were used to assess internal validity. After screening, 07 studies were included for data synthesis. For marking, four studies used LIGA clips, two used 5-mm cut pieces of K-wire, and one used cut pieces of 25-G needle. Incidence of unsatisfactory margins (positive/close) ranged from 0 to 11%. All studies found these low-cost markers to be feasible, with 100% pre-surgery visibility and 100% retrieval rate. Low-cost radio-opaque tumor markers (LIGA clips, 5-mm cut pieces of K-wire and 25-G needle) are effective methods of tumor localization especially for LMICs.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13193-023-01845-2.
Keywords: Breast cancer, Neoadjuvant chemotherapy, Radio-opaque tumor markers, Tumor mapping, Breast conservation surgery
Introduction
Breast cancer patients present with locally advanced stage or with high average tumor size in majority of low- and middle-income countries (LMICs) [1, 2]. Hence, neoadjuvant chemotherapy (NACT) is being increasingly used for these patients in the management to help in decreasing the tumor size, promoting breast conservation surgery, and converting large inoperable lesions into operable ones [1]. Patients have variable response to NACT including pathological complete response (pCR) which makes the tumor impalpable [3]. Radiopaque markers are used to mark the tumour site prior to the initiation of NACT to help the surgeon to excise the original tumour bed. Many techniques have been described for the pre-NACT tumour mapping ranging from skin tattooing, radio-opaque wires around the tumour, radio-opaque dyes, radioactive pellets to indigenous, and cost-effective radio-opaque markers [4–7]. Herein, we present a systemic review of low-cost tumour localization techniques.
Methods
Search Strategy
Authors designed a search protocol to identify evidence relevant to this review in accordance with PRISMA guidelines [8]. PubMed, EMBASE, and Cochrane database were reviewed from its inception till 30th November 2022. Two reviewers (BS and SKY) conducted the comprehensive electronic search (Appendix 1). Titles and abstracts were screened for eligibility by both reviewers. After excluding irrelevant studies, duplicate studies, review articles, case reports, editorials, and letters to the editor/correspondences, full texts were retrieved. Each article was coded as eligible, ineligible, or doubtful after reading the full text. All disagreements were resolved via discussion among all reviewers through online consultation.
Inclusion criteria.
Study designs: clinical trials, cohort studies, observational studies.
Participants: all patients of breast cancer who received NACT after marking the tumour
Patients included in the study must have undergone BCS.
Pre-surgery visibility and retrieval data were provided.
Studies describing low-cost techniques of tumour marking
There is no uniform definition of what low cost is. Reviewers agreed through consensus to accept the definition given by Hindocha et al. [9] that quality solutions in a resource-constrained environment that are affordable to low-income consumers are low cost or frugal innovation. For the purpose of this review, it was agreed upon that if any non-commercial tumour marker is used to decrease the cost of tumour mapping as compared to commercially available markers, then it is low cost.
Exclusion criteria.
Study designs: case reports were excluded.
Participants: patients of carcinoma breast who underwent primary surgery without NACT or did not undergo tumour marking
Statistical Method and Data Analysis:
The primary outcome of included studies was rate of successful localization at the time of surgery, and secondary outcome measures were rate of unsatisfactory margin post-NACT pre-surgery visibility and retrieval. Oxford Centre for Evidence Based Medicine (OCEBM) level of all studies was recorded to assess internal validity. Meta-analysis could not be performed because of the heterogeneity among the included studies in the study designs and marking techniques.
Results
As per our pre-defined criteria, seven articles were eligible for inclusion (Fig. 1) [10–16]. The characteristics of the included studies and their levels of evidence are listed in Table 1. All studies were rated at level 4 (evidence from well-designed case–control or cohort studies) according to the OCEBM [17].
Fig. 1.
The number of articles eligible for inclusion
Table 1.
Characteristics of included studies
| Study | Julia L.Oh et al Texas USA (2007) |
Inyoung Youn et al South Korea (2015) |
Rafia Shahzad et al Pakistan (2019) |
Manoj pandey et al India (2021) |
Anila Rahim et al Pakistan (2022) |
Abdelfatah et al Egypt (2022) |
Minella C et al Italy (2022) |
|---|---|---|---|---|---|---|---|
| Type of Study | Retrospective (univariate and multivariate analysis) | Prospective | Prospective | Prospective | Retrospective | Prospective | Prospective |
| Number of patients | 145 | 15 | 30 | 18 | 39 | 45 | 51 |
| Radiological modality | USG |
USG MRI |
USG | - | USG |
Sonomammography CE-MRI |
Sonomammography |
| Radio-opaque marker used | K wire | Ligaclip | Metallic clip made up of 25G needle | K wire | Ligaclip | Ligaclip | Ligaclips |
| OCEBM* | 4 | 4 | 4 | 4 | 4 | 4 | 4 |
| Cost in USD/case | NR | 10 | NR | NR | NR | 1.3 | NR |
| Feasibility | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| Pre-surgery visibility | 100% | 100% | 100% | 100% | 100% |
Visible- 55 lesions Artifact- 2 |
100% |
| Retrieval | 100% | 100% | 100% | 100% | 100% | 100% | 100% |
| Complications | Nil | Nil | Nil | Nil | Nil |
Hematoma-2 Clip migration-2 |
Clip migration-2 |
*OCEBM = Oxford Centre for Evidence Based Medicine
Method of Marking
Four studies used commercially available LIGA cholecystectomy clips as radio opaque marker, two studies used stainless steel K-wire cut into 5 mm pieces, and one used 25-G syringe needle cut into small pieces.
Localisation at the Time of Surgery
All studies reported excellent (~ 100%) pre-surgery visibility of the markers. Marker migration was reported in total of 4 patients (1%) but it did not affect the ability to excise the mass completely (Table 3).
Table 3.
Pooled margin status, retrieval, localization and feasibility rates
| S.No | Parameter | n | % |
|---|---|---|---|
| 1 | Unsatisfactory margins (%) | 17/328 | 5% |
| 2 | Localization | 343/343 | 100% |
| 3 | Retrieval | 343/343 | 100% |
| 4 | Feasibility | 343/343 | 100% |
Margin Status
The incidence of unsatisfactory margins (positive/close) in the included studies ranged from 0 to 11% (Table 2). Five studies reported pathological response and margin status. Among the 328 patients included in this review, 17 (5%) were reported to have unsatisfactory margins [Table 3]. Ninety of the included patients had a complete pathological response. Since these patients cannot have an unsatisfactory margin, we calculated the “adjusted unsatisfactory margin” rate by excluding these patients. The adjusted unsatisfactory margin rate was found to be 7%.
Table 2.
Margin status
| Serial number | Author | Number of patients undergoing BCS | pCR# (%) | Definition of unsatisfactory margin | Unsatisfactory margins (%) |
|---|---|---|---|---|---|
| 1 | Oh JL | 145 | 37(25.5) | < 2 mm | 16(11.0) |
| 2 | Inyoung Youn et al | 15 | NR | NR | NR |
| 3 | M Pandey | 18 | 00 | NR | 00 |
| 4 | A Rahim | 39 | 12(30.8%) | NR | 00 |
| 5 | R Shahzad | 30 | 9(28.1%) | NR | 00 |
| 6 | Carola Minella | 51 |
Breast-26/54 (48.1%) Axilla – 17/38 (44.7%) Overall – 13/38 (34%) |
NR | 1 /26 (3.8%) |
| 7 | Abdelfatah | 45 | 6 (13.3%) | NR | NR |
NR = Not reported, pCR = pathological complete response
Feasibility, Migration, and Retrieval
All studies reported 100% feasibility in radio-opaque marker placement before the start of NACT. All studies reported 100% retrieval rate.
Discussion
Our review identified that several low-cost innovative methods for tumour mapping have been described prior to the start of NACT and all were found effective.
The primary aim of tumour marking prior to NACT is to guide the surgeon to excise the mass with a satisfactory margin. The unsatisfactory margin rate was 5% (range: 0–11%) in this review. This was 16.7% and 23.5% in studies where commercial metallic coils and harpoons were used respectively [5, 18]. Similarly, studies using 125I-radioactive seeds (RSL) have reported the unsatisfactory margin rate ranging from 8.2 to 19.2% [6, 19, 20]. Radio-guided occult lesion localization using 99mTc (ROLL) was utilized as the marker by Donker et al. [7]. Authors reported an unsatisfactory margin rate of 13.3%. Hence, the rate of unsatisfactory margin by low-cost tumour mapping techniques compares favourably with commercially available markers.
The cost of RSL and ROLL ranges from 100 to 250 USD apart from initial set-up as it involves a time-consuming regulative route because of its radioactive nature [21]. Recently, magnetic seed localization (MSL) is being advocated in developed countries [22, 23]. However, this has not been evaluated in patients undergoing NACT and reported cost is over 200 USD [21]. Commercially available metallic coils used for tumour marking cost around 50 USD [24]. As compared to these commercial markers, low-cost tumour markers identified in this review are very economical. For example, LIGA clips cost between 5 and 10 USD in India. Similarly, 5-mm cut pieces of K-wire marker described by Biswas et al. [13] and Julia et al. [10] costs only 1–2 USDs. Metallic clip made of 25-G needle used as tumour marker costs even less than a USD [12].
The only major disadvantage of 25-G needle low-cost metallic radio-opaque markers is that it is MRI incompatible. However, LIGA clips and K wires made of titanium are MRI compatible. Due to limited resources, a very small number of patients undergo MRI, and hence, all three can be used in majority of LMICs.
The major limitation of our review is that studies were not available to compare the commercial markers with low-cost markers. Cost of most of the markers was not mentioned, and these were calculated as per Indian market. Information on at what point before or during neoadjuvant chemotherapy, the marker was inserted, and average tumour size was not provided. Furthermore, except for one study with 145 patients, the majority of the studies involved small numbers, ranging from 15 to 51 cases, with a mean of 33 cases, and definition of unsatisfactory margin was not provided by all studies. However, unsatisfactory margins are not a valid outcome for any marker — even if the most expensive marker was used, it is the skill of the localization (when there is a complete clinical response) and the skill of the surgeon which will determine margins. Hence, despite these limitations, our systematic review clearly shows that low-cost radio-opaque tumour markers are effective and can be incorporated in a standard surgical pathway for early breast cancer in limited resource settings. [25]
Conclusion
Low-cost radio-opaque tumour markers (LIGA clips, 5-mm cut pieces of K-wire, and 25-G needle) are effective methods of tumour localization especially for LMICs.
Supplementary Information
Below is the link to the electronic supplementary material.
Author Contribution
BS and SKY: literature search, figures, study design, data collection, data analysis, data interpretation, writing. DS: Revision and editing of manuscript.
Declarations
Informed Consent
Not applicable.
Research Involving Human Participants and/or Animals
Not applicable.
Conflict of Interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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