Elsevier

Clinical Breast Cancer

Volume 17, Issue 5, August 2017, Pages 399-402
Clinical Breast Cancer

Current Trial Report
A Novel Less-invasive Approach for Axillary Staging After Neoadjuvant Chemotherapy in Patients With Axillary Node-positive Breast Cancer by Combining Radioactive Iodine Seed Localization in the Axilla With the Sentinel Node Procedure (RISAS): A Dutch Prospective Multicenter Validation Study

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Abstract

Background

In 1 of 3 patients with initial lymph node-positive (cN+) breast cancer, neoadjuvant chemotherapy (NAC) results in an axillary pathologic complete response (ax-pCR). This urges the need for a less-invasive axillary staging method. Recently introduced less-invasive procedures have been insufficient in accurately identifying ax-pCR. Therefore, we propose a novel less-invasive axillary staging procedure: the Radioactive Iodine Seed localization in the Axilla with the Sentinel node procedure (RISAS), a combination of the procedure of marking axillary lymph nodes with radioactive iodine seeds (MARI) and sentinel lymph node biopsy (SLNB).

Patients and Methods

In the present open single-arm multicenter validation study, 225 cN+ (biopsy-proven) patients will undergo the RISAS procedure, in which a positive lymph node is marked by an iodine-125 seed before NAC. After NAC completion, this iodine-125 seed-marked lymph node is removed, together with any additional sentinel lymph nodes. The RISAS procedure is subsequently followed by completion axillary lymph node dissection (ALND). The RISAS lymph nodes will be compared with the lymph nodes from the completion ALND specimen. The primary endpoint is accuracy of the RISAS procedure. The identification rate, false-negative rate, negative predictive value, and possible concordance between the MARI and SLNB will be reported.

Conclusion

The present prospective multicenter RISAS trial will enable us to validate the combination of MARI and SLNB for assessing the axillary response to NAC in cN+ patients. If RISAS proves to be an accurate axillary staging procedure, ALND could safely be abandoned in the case of ax-pCR confirmed using the RISAS procedure.

Introduction

Surgical management of the axilla in breast cancer has evolved greatly in the past decades. In clinically node negative patients, axillary staging has shifted from axillary lymph node dissection (ALND) to sentinel lymph node biopsy (SLNB). In clinically node positive patients (cN+), ALND is still recommended for axillary staging.1, 2 However, the shift from adjuvant to neoadjuvant chemotherapy (NAC) has resulted in an increasing need for a less-invasive axillary staging approach, because NAC enables downstaging of axillary disease.3, 4 In ≤ 36% of all patients, conversion of cN+ to an axillary pathologic complete response (ax-pCR) as a result of NAC has been reported.5 In the case of HER2/neu+ patients, ax-pCR can be achieved in ≤ 74% of patients when NAC is combined with HER2-targeted therapy.6, 7 Patients in whom ax-pCR is achieved are not expected to benefit from ALND; however, a significant proportion will experience side effects. Consequently, routine ALND is increasingly being regarded as overtreatment in these patients.

To date, imaging techniques have not been able to accurately identify the presence of an ax-pCR. As for surgical techniques, various less-invasive axillary staging procedures have been proposed for cN+ patients after NAC completion. The SLNB seems to be insufficient, with reported false-negative rates (FNRs) ranging from 7%8 to 25%.9 Because the SLNB aims to identify patients with an ax-pCR without missing residual disease, a negative predictive value (NPV) of ≥ 95% would be desirable. A high NPV is especially important because residual tumor is considered resistant to administered chemotherapy and might require additional treatment. However, the NPVs for SLNB have not exceeded 86%5; thus, residual axillary disease will be missed in 1 of every 6 patients for whom an ax-pCR is suggested by the SLNs. Factors contributing to the improvement of the FNR/NPV of SLNB include using the dual tracer technique and removal of ≥ 3 SLNs.8, 10, 11, 12 In daily practice, the latter is not always achievable, which was demonstrated by the SENTINA (sentinel neoadjuvant) trial, in which most patients had only 1 to 2 SLNs removed.12 Donker et al13 introduced an alternative, less-invasive axillary staging procedure: the MARI procedure (marking axillary lymph nodes with radioactive iodine seeds). In the MARI procedure, an iodine-125 (125I) seed is placed in the biopsy-proven positive axillary lymph node before NAC. After NAC completion, the 125I seed-containing lymph node is removed at breast surgery. In 98 pretreatment cN+ patients, an identification rate of 97% and an FNR of 7% was reported. The MARI procedure has a reported NPV of 83%, indicating that residual axillary disease is still overlooked to the same extent as with the SLNB.13, 14 In summary, both the MARI and SLNB remain insufficiently accurate to use as solitary staging procedures.

Caudle et al15 proposed targeted axillary dissection (TAD), involving clip placement in a biopsy-proven positive axillary lymph node before NAC, followed by localization of this clipped node with a 125I seed after NAC completion. Excision of the 125I seed-marked node was combined with excision of SLNs. All cN+ patients treated with NAC and in whom the biopsied node was marked with a clip were included in a prospective registry. Retrospectively, 85 patients who had undergone TAD, followed by completion ALND, were identified. A FNR of 2% and a NPV of 97% were reported.15 These results are promising; however, the study was hampered by the single-center study design and small sample size, with only 35 patients in whom an ax-pCR was achieved. Consequently, widespread implementation of TAD cannot be recommended before a large, preferably multicenter, validation study has been performed.

Therefore, we propose a multicenter, open, single-arm validation study in which the RISAS (Radioactive Iodine Seed localization in the Axilla combined with the SLNB) procedure is investigated. To validate RISAS, completion ALND will be performed in all patients. The 125I seed will be placed before the start of NAC. If the results prove that RISAS accurately predicts axillary nodal status after NAC completion, completion ALND and its concomitant morbidity can safely be omitted and prevented in patients with an ax-pCR predicted by RISAS.

Section snippets

Patients and Methods

The RISAS study is an open, single-arm, noninferiority multicenter validation study to assess the accuracy of RISAS for axillary staging after NAC in pretreatment cN+ breast cancer patients. Nodal positivity will always be confirmed by pathologic assessment before the start of NAC in the case of suspicious lymph nodes found on axillary ultrasonography. Patients will be recruited from approximately 8 participating hospitals in the Netherlands during a 2-year period. Each hospital has ≥ 1 year of

Discussion

With the increasing need for less-invasive axillary staging after NAC, various procedures have been proposed. MARI and SLNB remain insufficient for this purpose, because they miss potentially therapy-resistant disease to a rather high extent.5, 11, 13 TAD has shown promising results; however, owing to the retrospective analysis of patients and small sample size of the single-center study, it seems premature to implement this procedure as standard practice in replacement of ALND.15 Our present

Conclusion

The RISAS study is a multicenter prospective noninferiority study to validate the combination of MARI and SLNB for predicting the axillary response to NAC in pretreatment cN+ patients. The ultimate goal is to identify ax-pCR patients using a minimally invasive procedure to prevent unnecessary ALND, with its associated side effects, without comprising oncologic safety. ALND could then become a management procedure reserved for patients with residual axillary disease.

Disclosure

The authors have stated that they have no conflicts of interest.

Acknowledgments

The present study received grant support from the Alpe d'Huzes/Dutch Cancer Society (KWF Kankerbestrijding) fund (grant AZB 2015-8023).

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T.J.A.v.N., J.M.S., L.B.K. and E.J.T.L. contributed equally to this work.

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