Registry Trial to Evaluate the Clinical Utilization of Targeted Axillary Dissection (TAD)

Study Overview
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Brief Summary
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A downstaging of axillary tumor-spread can be achieved in about 40% of the patients receiving neoadjuvant chemotherapy (NACT). The impact of NACT on loco-regional tumor control has not yet been sufficiently investigated. Moreover the pathologic nodal status after NACT is a strong prognostic marker. Therefore it is most desirable to identify the approximately 40% of patients with pathologic complete response of the axilla, that could be spared from a potentially non beneficial axillary lymph node dissection (ALND). Attempts to identify these patients via sentinel lymph node biopsy (SLNB) after NACT have failed to provide acceptable false negative rates (FNR). The new concept of targeted axillary dissection (TAD) following NACT has shown promising results. Still multiple information about the clinical adoption of this procedure into clinical practice are missing. The SenTa registry trial is designed to assess the clinical implementation of TAD into general practice.

Detailed Description
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For decades the pathologic nodal status in early breast cancer has been of paramount importance, when evaluating the need for further adjuvant therapies. Nowadays tumor characteristics as receptor status and gene expression essays are increasingly included in this decision process. An increasing number of breast cancer patients are treated with neoadjuvant chemotherapy (NACT). A downstaging of axillary tumor-spread can be achieved in about 40% of the patients receiving NACT. The contribution of NACT to loco-regional tumor control is not fully integrated into the surgical treatment plan. The introduction of sentinel lymph node biopsy (SLNB) and the results of the ACOSOG (American College of Surgeons Oncology Group) Z0011 trial led to a reduction in radicalness of axillary surgery in the adjuvant setting. The impact of NACT on loco-regional tumor control in the neoadjuvant setting has not yet been sufficiently investigated. Moreover the pathologic nodal status after NACT is a strong prognostic marker. Therefore it is most desirable to identify the approximately 40% of patients with pathologic complete response of the axilla and distinguish these patients from those with tumor residuals which might need additional postneoadjuvant treatment. So far attempts to identify these patients via SLNB after NACT have failed to provide acceptable false negative rates (FNR) as reported in the SENTINA (Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy) trial and ACOSOG Z1071 trial. Attempts have bee made to further improve FNR of SLNB after NACT in patients with clinically affected lymph nodes at initial presentation. A new concept of surgical axillary staging after NACT is the targeted axillary dissection (TAD). First results have shown to reduce FNR far below the desired threshold of 10%. In this procedure clinically suspicious lymph nodes are evaluated by core needle biopsy (CNB) or fine needle aspiration (FNA) before NACT. A clip is placed into the most suspicious appearing lymph node (target lymph node TLN) directly after biopsy. In case of proven metastasis surgical staging of the axilla is postponed to after completion of NACT. The targeted resection of the clipped node after NACT (target lymph node biopsy TLNB) displays a FNR of 2 - 4.2% according to first results published by Caudle et al. in 2016. In about 3 out of 4 patients the TLN equals a SLN if SLNB is performed simultaneously. The combination of TLNB and SLNB (together so called TAD) seems to further lower FNR. Cases in which tracer uptake in lymph nodes is impaired i.e. by tumor residuals and presumably result in a false negative SLNB can be covered by TLNB. Clip placement in affected axillary lymph nodes for the purpose of following targeted resection has been implemented into international guidelines. But to date multiple insights into clinical application of TAD are missing. It is not known how often initial CNB/FNA of axillary lymph nodes and following clip placement is successful or has to be abandoned because of technical/medical contraindications. Moreover it is not known how often visualization of the clip after normalization of lymph node structures following NACT and month after initial clip placement is possible. Furthermore information about optimal clip material are lacking. In summary success rates for the targeted resection of the clipped node have to be investigated. Therefore the intraoperative detection rate of the clipped target lymph node is our primary outcome measure. Patients with clinically affected lymph nodes at initial presentation are planned to be enrolled in multiple german breast centers. In accorndance to german guidelines it is aimed to evaluate the pathologic nodal status via CNB with following clip placement in all of these patients after informed consent. If CNB or clip placement cannot be achieved, technical/medical contraindications are recorded. As the SenTa trial is a registry trial, no strict directives for the further surgical treatment are made. If clip placement is successful, further procedures are left at the investigators choice according to initial pathologic nodal status and potential clinical response to NACT. If no tumor manifestations are detected in initial CNB, SLNB with simultaneous targeted resection of the clipped node (TLNB) is recommended. The rationale for TLNB in this situation is a FNR of about 20% of initial CNB. On an individual basis upfront ALND can be offered. If tumor manifestations are detected in initial CNB, targeted resection of the clipped node (TLNB) is strongly recommended because of obvious reasons. If NACT is not planned, upfront ALND should be offered. If patients are planned for NACT further procedures are left at the investigators discretion according to clinical response to NACT. Clinical response after NACT is assessed by axillary ultrasound and an optional needle biopsy if applicable. In case of clinical complete response, TLNB with simultaneous SLNB can be offered on an individual basis.

Official Title
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A Prospective, Multicenter, Registry Trial to Evaluate Utilization Frequency and Feasibility of Targeted Axillary Dissection (TAD) After Needle Biopsy and Clip Placement in Early Breast Cancer With Clinically Affected Lymph Nodes

Conditions
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Early Stage Breast Cancer

Intervention / Treatment
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* Other: Not suitable for TAD
* Procedure: Suitable for TAD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria informed consent invasive mamma carcinoma verified by needle biopsy of the primary tumor nodal positive (cN+) verified by axillary ultrasound cT stage 1-4c, multifocality allowed no sign of distant metastasis (cM0) Exclusion Criteria: prior history of breast cancer prior ipsilateral extensive surgery of breast or axilla inflammatory or extramammary breast cancer pregnancy inability to understand the studies purpose no written patient informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CNB biopsy/clip placement not done<br>Clinically affected lymph nodes cannot be biopsied or clip labeled. Patients are not suitable for TAD | Other: Not suitable for TAD<br>* Registry of the rate of patients not suitable for TAD as initial CNB with clip placement of axillary lymph nodes is not possible and underlying medical contraindications, technical obstacles or miscellaneous reasons why needle biopsy and/or clip labeling of clinically affected lymph nodes cannot be done<br>|
| CNB/clip placement done - benign<br>Clinically affected lymph nodes can be biopsied and clip labeled. Needle biopsy reveals no axillary tumor spread. Patients are suitable for TAD | Procedure: Suitable for TAD<br>* Registry of surgical outcome measures of targeted resection of the clipped node with optional sentinel node biopsy or axillary lymph node dissection with or without preceding neoadjuvant chemotherapy<br>|
| CNB/clip placement done - malignant<br>Clinically affected lymph nodes can be biopsied and clip labeled. Needle biopsy reveals axillary tumor spread. Patients are suitable for TAD | Procedure: Suitable for TAD<br>* Registry of surgical outcome measures of targeted resection of the clipped node with optional sentinel node biopsy or axillary lymph node dissection with or without preceding neoadjuvant chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical detection rate of the clip labeled target lymph node | Successful intraoperative detection and targeted resection of clip labeled target lymph node as confirmed by specimen radiography and/or surgeon | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of patients not suitable for targeted axillary dissection (TAD) | Rate of patients not suitable for TAD as initial CNB with clip placement of axillary lymph nodes is not possible and underlying medical contraindications, technical obstacles or miscellaneous reasons why needle biopsy and/or clip labeling of clinically affected lymph nodes cannot be done | 14 days | 
| Rate of representative and successful lymph node CNB | Rate of CNB revealing tumor manifestations or lymph node tissue on histology out of all performed lymph node CNB | 14 days | 
| Rate of preoperative sonographic clip detection | Essential requirement for targeted resection of the clipped target lymph node is the preoperative visualization of the clip for the purpose of guide wire localization | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| Rate of patients treated with TAD after NACT | Rate of patients with intraoperative detection of at least one sentinel lymph node and the clip labeled target lymph node as confirmed by specimen radiography and/or surgeon | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| Rate of patients treated with upfront ALND after NACT | Rate of patients treated with upfront axillary dissection including resection of clipped node after completion of NACT | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| False negative rate for target lymph node biopsy (TLNB) alone | Clipped target lymph node does not contain tumor manifestations after NACT but lymph node metastasis is revealed by ALND | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| False negative rate for Sentinel Lymph Node Biopsy (SLN) alone | Sentinel lymph node does not contain tumor manifestations after NACT but lymph node metastasis is revealed by ALND | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| Detection Rate for Targeted Axillary Detection (TAD) (SLN and TLN detected) | Successful intraoperative detection and resection of at least one sentinel lymph node and the clip labeled target lymph node as confirmed by specimen radiography and/or surgeon | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| Detection Rate for Sentinel Lymph Node Biopsy (SLNB) | Successful intraoperative detection and resection of at least one sentinel lymph node | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| Rate of patients,where the clip is found in a sentinel lymph node (SLN) | Clip is located in a sentinel lymph node during TAD, hence the TLN equals a SLN | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| Number of excised lymph nodes during targeted axillary dissection (TAD) | Number of excised lymph nodes during targeted axillary dissection (TAD) equals count of sentinel lymph nodes plus target lymph nodes | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| Number of excised lymph nodes during sentinel lymph node biopsy (SLNB) | Number of excised lymph nodes during targeted axillary dissection (TAD) equals count of sentinel lymph nodes plus target lymph nodes | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 
| Number of excised target lymph nodes (TLN) which are not a sentinel lymph node | Number of excised clipped lymph nodes during target lymph node biopsy (TLNB) which are not sentinel lymph nodes | 6 month for patients undergoing NACT after initial needle biopsy/clip placement and subsequent surgical resection of the clipped node | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Targeted axillary dissection, Sentinel node biopsy, Neoadjuvant chemotherapy