Optimising the targeted axillary dissection in breast cancer: marker type and timing variability

Introduction

The systematic review conducted by de Wild et al. provides an in-depth exploration of targeted axillary dissection (TAD) in patients with node-positive breast cancer treated with neoadjuvant systemic therapy (NST) (1). This comprehensive analysis addresses two key heterogenous aspects of the TAD technique—marker types and the timing of their placement. By evaluating these aspects, the review discusses whether TAD accuracy is potentially influencing subsequent treatment decisions. As breast cancer surgery continues to evolve, this review sheds light on the difficulty to ascertain the optimal technique in TAD.

The development of TAD

The increasing utilization of NST has revolutionized breast cancer treatment, particularly in patients with triple negative breast cancer, Her2 positive breast cancer and locally advanced disease, with international guidelines standardising its usage (2-4). The provision of NST can lead to treatment response adjustments in surgical and other adjuvant therapies. Response to NST often defines adjuvant systemic therapy especially for triple negative and Her2 positive cancers, it increases rates of breast conservation surgery across all subtypes of breast cancer, allows time for genetic testing and co-ordination and suitability for immediate breast reconstruction in patients still needing mastectomy. Crucially, depending on tumour subtype, there is up to a 60% chance of achieving a pathological complete response (pCR) in the axilla and/or breast (5). In the presence of a pCR, or very low residual volume nodal disease, the need to perform a morbid axillary lymph node dissection has been questioned (5). Consequently, there is a growing need for precise and reliable techniques, which are less invasive, to assess the axillary response to NST.

The TAD technique, first described by Straver et al. in 2010, involved using Iodine-125 labelled seeds to detect the pre-NST biopsy-proven positive axillary node intraoperatively (6). This method, known as the “Marking the axilla with radioactive seeds (MARI) procedure” achieved a 97% success rate in removing the clipped node in a later cohort study (7). Subsequent studies, such as Caudle et al. [2016] identified a comparable 96% success rate (8). The first published meta-analyses discussing TAD have focused on the false negative rate of the procedure, descriptively discussing the different techniques, yet never statistically evaluating them (9,10). Since the seminal article by Straver et al., the literature has discussed many varied techniques to identify the positive node, with no statistically superior technique to date (11). Indeed, with the differences in local specialization skill sets in individual health facilities, it is unlikely that any particular technique will be best in all settings.

Objective of the review

de Wild et al. aimed to systematically review the TAD literature, defined as a procedure that combines sentinel lymph node biopsy (SLNB) with targeted removal of a previously biopsy-proven metastatic lymph node. The primary objective was to evaluate the variations in the type of markers used for localization and the timing of their placement. The review sought to determine the impact of these variables on the identification rates of targeted lymph nodes (TLNs) and to provide insights into optimizing TAD protocols.

Methodological approach

The review followed a rigorous methodological framework, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search strategy of PubMed and Embase was employed to identify relevant studies, identifying 277 studies. Ultimately, 51 studies involving a total of 4,512 patients were included in the qualitative analysis. The inclusion criteria were stringent, focusing on node-positive studies that utilized TAD in combination with SLNB only, ensuring the relevance and specificity of the findings.

The quality of the included studies was assessed using the National Institutes of Health (NIH) quality assessment tool. Most studies were rated as fair quality, reflecting the inherent challenges in conducting high-quality research in this dynamic field. Despite these limitations, the review provides a valuable synthesis of current practices and highlights areas requiring further investigation.

Findings and clinical implications

The review identified multiple distinct types of markers used in TAD: hook-wire, 125I-labelled seeds, ultrasound guided 99mTc injections, magnetic markers, electromagnetic reflectors, radiofrequency identification (RFID) tags, black ink, and a clip (combined with intraoperative ultrasound). Each marker type has unique characteristics, influencing its efficacy and feasibility in clinical practice and was beyond the scope of the study. The analysis revealed considerable variability in the identification rates of TLNs at surgery, which were influenced by the type of marker and the timing of its placement.

Marker types and their efficacy

The efficacy of different marker types in TAD is a critical consideration for optimizing the removal of the TLN. Wire localization, one of the earliest techniques used, offers straightforward placement and retrieval but may be associated with patient discomfort, haematoma, adjacent tissue injury, and a higher risk of marker migration (12). 125I-labelled seeds provide excellent localization accuracy with minimal migration, but they require specialized handling and disposal due to their radioactive nature (13,14).

The usage of 99mTc, commonly used in SLNB, offer dual utility for TAD by enabling both lymphoscintigraphy and intraoperative gamma probe detection of the TLN simultaneously, without requiring alternative equipment (15). The ability to minimise costs by maximising current equipment utilisation is very efficient, however overall efficacy may be negatively influenced by factors such as injection technique and needing to time injection relative to surgery.

Magnetic seeds, reflectors and radiofrequency markers represent newer technologies that offer promising results in terms of localization accuracy and ease of use. These markers do not involve radiation, enhancing their safety profile, but require specific detection equipment. Of note, the magnetic seeds and RFID tags have an identifiable bloom on Magnetic Resonance Imaging, which limits the ability to adequately assess axillary response to NST if inserted as a one-step procedure (16).

Clips are particularly advantageous for marking the lymph node due to their stability and compatibility with various imaging modalities. A key limitation though is compromised clip visibility if the node is deep in the axilla with resolution of lymph node cortical thickening making ultrasound identification of the clipped node even more challenging (17). Furthermore, there is a requirement for the surgeon to be trained and confident in ultrasound guided surgery to ensure node excision without clip extrusion. The optimal timing for clip placement remains a subject of debate, as pre-NST placement may risk displacement during therapy, while post-NST placement may complicate accurate localization.

Some articles have discussed comparisons between differing marker techniques used for TAD. Nguyen et al. discussed the Australian experience of using SCOUT^® radar localisation, compared to hook-wire, identifying a cost-effectiveness once more than 300 cases have been performed (18). The benefit of decoupling radiology and theatre schedules, has previously been discussed, and was evident with a median 3-day radar placement before surgery, compared to the wire-localisation placement within a day of surgery (14). Žatecký et al. compared iodine seed, magnetic seed and carbon localisation in a cohort of 189 patients undergoing TAD (19). They failed to identify any statistically significant difference when comparing marker implantation rates of complication, detection, or dislodgement.

One-step vs. two-step procedures

The review also discussed an important consideration of the TAD procedure, whether performed in one or two-steps based off the final marker placement timing. In one-step procedures, the definitive marker is placed in the TLN before the initiation of NST. This approach ensures that the marker is present throughout the entire course of systemic therapy, facilitating accurate localization at the time of surgery. One-step procedures demonstrated identification rates ranging from 61.54–100%, reflecting the variability in clinical practice and marker performance.

In contrast, two-step procedures involved post-NST placement of a marker adjacent to a pre-NST clip. This approach aims to address the potential displacement or loss of the initial marker during NST. Identification rates for two-step procedures varied widely from 70.83–100%. The variability highlights the challenges associated with accurately re-localising the TLN after systemic therapy.

Challenges and limitations

Despite the comprehensive nature of this review, several challenges and limitations must be acknowledged. The heterogeneity of the included studies, in terms of study design, patient populations, and marker types, complicates direct comparisons and synthesis of the findings. Most studies were rated as fair quality, reflecting the inherent difficulties in conducting high-quality research in this field. Variability in surgical expertise, imaging modalities, and institutional protocols further complicates the interpretation of these results.

Moreover, the review highlights a critical gap in the literature - the lack of standardized protocols for TAD. The variations in marker types, timing of placement, and identification rates underscore the need for consensus guidelines to define acceptable parameters that indicate an institution is meeting “best practice” standards at doing the procedure by whatever method they are using. Future research should theoretically focus on large-scale randomized controlled trials comparing different marker types and timing strategies to establish evidence-based standards; however, this will be highly unlikely to be achieved given each institution will have their own reasoning for their marker type and timing due to inherent politics and fiscal constraints. TAD registry studies, such as those occurring in Europe and Australia, will give insights into the uptake and the application of the procedure across multiple institutions rather than the current predominance of single institution experiences (20,21).

Conclusions

The systematic review by de Wild et al. provides a valuable synthesis of current practices in TAD for node-positive breast cancer patients treated with NST. The identified variability in marker types and timing underscores the complexity of optimizing this axillary staging technique. As the field continues to evolve, ongoing research and standardization efforts are crucial to refining TAD protocols, improving patient outcomes, and reducing the morbidity associated with axillary surgery.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery. The article has undergone external peer review.

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-279/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-279/coif). A.O. reports that he has received a Breast Cancer Trials Clinical Research Fellowship Stipend for 24 months and received support for attending the 2023 Breast Cancer Trials meeting. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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