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10.1245/ASO.2006.07.025
Annals of Surgical Oncology 13:475-479 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Sentinel Node Biopsy Before Neoadjuvant Chemotherapy Spares Breast Cancer Patients Axillary Lymph Node Dissection

Maartje C. van Rijk, MD1, Omgo E. Nieweg, MD, PhD1, Emiel J. T. Rutgers, MD, PhD, FRCS1, Hester S. A. Oldenburg, MD, PhD1, Renato Valdeés Olmos, MD, PhD2, Cornelis A. Hoefnagel, MD, PhD2 and Bin B. R. Kroon, MD, PhD, FRCS1

1 Department of Surgery, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
2 Department of Nuclear Medicine, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

Correspondence: Address correspondence and reprint requests to: Maartje C. van Rijk, MD; E-mail: m.v.rijk{at}nki.nl.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Neoadjuvant chemotherapy in breast cancer patients is a valuable method to determine the efficacy of chemotherapy and potentially downsize the primary tumor, which facilitates breast-conserving therapy. In 18 studies published about sentinel node biopsy after neoadjuvant chemotherapy, the sentinel node was identified in on average 89%, and the false-negative rate was on average 10%. Because of these mediocre results, no author dares to omit axillary clearance just yet. In our institute, sentinel lymph node biopsy is performed before neoadjuvant chemotherapy. The aim of this study was to evaluate our experience with this approach.

Methods: Sentinel node biopsy was performed before neoadjuvant chemotherapy in 25 T2N0 patients by using lymphoscintigraphy, a gamma ray detection probe, and patent blue dye. Axillary lymph node dissection was performed after chemotherapy if the sentinel node contained metastases.

Results: Ten patients had a tumor-positive axillary sentinel node, and one patient had an involved lateral intramammary node. Four patients had additional involved nodes in the completion lymph node dissection specimen. The other 14 patients (56%) had a tumor-negative sentinel node and did not undergo axillary lymph node dissection. No recurrences have been observed after a median follow-up of 18 months.

Conclusions: Fourteen (56%) of the 2 patients were spared axillary lymph node dissection when the sentinel node was found to be disease free. Performing sentinel node biopsy before neoadjuvant chemotherapy seems successful and reliable in patients with T2N0 breast cancer.

Key Words: Neoadjuvant chemotherapy • Sentinel lymph node biopsy • Metastases • Breast neoplasms • Lymphatic metastases • Lymph node dissection


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Neoadjuvant chemotherapy is traditionally given to patients with advanced breast cancer, but selected patients with earlier disease are currently also offered this treatment modality. This approach has two advantages: first, it is a valuable method to evaluate the efficacy of the chemotherapy regimen, and second, the tumor may be decreased in size, which facilitates breast-conserving therapy or makes it possible in patients who would otherwise need a mastectomy.1 Axillary lymph node dissection is typically performed after neoadjuvant chemotherapy, regardless of the tumor’s response. Because not all patients with a large breast cancer have involved axillary lymph nodes, several investigators have attempted to perform the sentinel node procedure after chemotherapy.2–5 Their aim was to determine the feasibility and reliability of the procedure in this group of patients.6–12

It is unclear what influence, if any, neoadjuvant chemotherapy may have on the lymph drainage pattern of the breast. Pending evidence of the safety of the procedure after neoadjuvant chemotherapy, we opted to perform lymphatic mapping before the chemotherapy. The aim of this study was to evaluate our experience with this approach.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Twenty-five patients were eligible for neoadjuvant chemotherapy and sentinel node biopsy. Table 1Go summarizes the characteristics of the tumors, the patients, and their treatment. Pathologic proof of breast cancer was obtained before surgery by either fine-needle aspiration cytological analysis or core biopsy. All patients had clinical stage II (T2N0) breast cancer. Patients with proven axillary metastases were not eligible. Before chemotherapy, ultrasonography of the axilla was performed, followed by fine-needle aspiration in case of a suspicious lymph node.


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  		TABLE 1. Patient, tumor, and treatment characteristics
 
Sentinel node biopsy was performed before chemotherapy. A 2-day protocol was used. On the day before surgery, 99mTc-nanocolloid (Nanocoll; Amersham Cygne, Eindhoven, The Netherlands) was injected into the lesion in a mean volume of .2 mL and with a mean radioactivity dose of 116 MBq (3.1 mCi). Static imaging was performed at 30 minutes, 2 hours, and 4 hours after injection. A dual-head gamma camera (Philips; Vertex, Eindhoven, The Netherlands) was used. Both anterior and prone lateral images were obtained. The location of the node was marked on the skin with indelible ink. During the operation, 1 mL of patent blue dye (Laboratoire Guerbet, Aulnay-Sous-Bois, France) was injected into the primary tumor. All sentinel nodes as visualized on lymphoscintigraphy were pursued with the aid of a gamma ray detection probe (Neoprobe; Johnson & Johnson Medical, Hamburg, Germany) and the blue dye. All procedures were performed by one of four experienced surgeons or under their supervision by a resident or fellow. The sentinel nodes were formalin-fixed, bisected, paraffin-embedded, and cut at a minimum of six levels at 50- to 150-µm intervals. Pathologic evaluation included hematoxylin-eosin and immunohistochemical staining (CAM 5.2; Becton Dickinson, San Jose, CA).

Most patients receiving neoadjuvant chemotherapy were enrolled in a prospective study and were randomized between six courses of conventional chemotherapy (doxorubicin/cyclophosphamide) or six courses with an anthracycline/taxane-based regimen (doxorubicin/docetaxel). The medical ethics committee of The Netherlands Cancer Institute approved this study, and informed consent was obtained from all patients. After three and six cycles of chemotherapy, the tumor was evaluated by physical examination and magnetic resonance imaging. Dependent on the results of these diagnostic tools, the decision whether or not to perform breast-conserving surgery was made. Radiotherapy to the breast was given in patients who underwent breast-conserving therapy. Adjuvant systemic hormonal therapy was offered to patients with a hormone receptor–positive tumor.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
All 25 patients had visualization of one or several sentinel nodes in the axilla. Four patients had additional sentinel nodes in the internal mammary chain, and five patients also had sentinel nodes in other locations. The axillary sentinel nodes were pursued and identified in all patients. An average of two sentinel nodes were removed (range, one to four). Of the patients with an involved sentinel node, on average 1.4 sentinel nodes were involved (range, 1–3). Sentinel nodes in the internal mammary chain were identified in three patients. Intramammary and interpectoral sentinel nodes were identified in three patients and one patient, respectively.

Pathologic evaluation revealed that 10 patients had an involved axillary node and 1 had an involved laterally situated intramammary node. Ten of these 11 underwent axillary lymph node dissection, and the remaining patient received radiotherapy of the axilla. An average of 12 nodes were removed when axillary node dissection was performed (range, 7–20). Four patients had additional involved nodes in the completion lymph node dissection specimen after neoadjuvant chemotherapy. Their mean number of involved nonsentinel nodes was three (range, one to six), and all four patients had involved nodes in level III of the axilla. Macrometastases, micrometastases, and submicrometastases were identified in the axillary lymph node dissection specimen. The patient who received radiotherapy to the axilla was tumor-free after 12 months of follow-up.

The remaining 14 patients had tumor-negative axillary sentinel nodes and did not undergo axillary lymph node dissection. No recurrences have been observed after a median follow-up of 18 months (range, 4–48 months).

Table 2Go summarizes the pathologic response rates of the tumors to the neoadjuvant chemotherapy. The two patients with pathologic complete remission of the primary tumor and tumor-positive sentinel nodes did not have residual disease in the axillary lymph node dissection specimen.


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  		TABLE 2. Pathologic tumor response to chemotherapy
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study shows that sentinel node biopsy can reliably be performed in patients with T2N0 tumors receiving neoadjuvant chemotherapy when the procedure is performed before treatment. The sentinel node was found in all 25 patients, 14 of whom were spared axillary node dissection because the sentinel node was disease free. None of them developed a recurrence. These numbers are at least as good as when sentinel node biopsy is performed in patients whose initial treatment is surgery.13–15

Several issues concerning our study can be disputed. The median follow-up was just 1.5 years; axillary recurrence may still happen. Lymphatic mapping before neoadjuvant chemotherapy may lead to both overstaging and understaging. On the one hand, there is the possibility that patients with an involved sentinel node who go on to develop a complete pathologic response will undergo an unnecessary node dissection because the chemotherapy cleaned up the other lymph node metastases.16 On the other hand, there is the possibility that dissemination to the lymph nodes occurs in the period between removal of a tumor-free sentinel node and the definitive breast surgery. Prechemotherapy sentinel node biopsy would then lead to insufficient treatment. However, the odds for either of these scenarios seem small,5 and other than an increased time between sentinel node biopsy and axillary lymph node dissection, the sentinel node biopsy before neoadjuvant chemotherapy is similar to the "standard" surgical management. Experience with >8000 published cases shows that only a few axillary recurrences have been encountered with routine sentinel node biopsy.15

So why have other investigators chosen to perform the sentinel node procedure after neoadjuvant chemotherapy? One reason is that the sentinel lymph node biopsy is then performed exactly at the time that the staging information matters.

With lymphatic mapping after neoadjuvant chemotherapy, the sentinel node identification rate is between 78% and 100% (Table 3Go), and this means that up to 22% of patients would be subjected to an axillary lymph node dissection that more than half do not need. Also, the false-negative rate is on average 10% (range, 0%–33%). There are differences in study design that might explain the broad range of the results. Some investigators injected the tracer peritumorally,15 and others used a periareolar injection technique.17 Some always use both a blue dye and a radioactive tracer,10 and others use only a radioactive tracer.18 One study included patients with clinically positive lymph nodes.10 Tumor size also varied between studies: some concerned patients with T1 and T2 tumors,19 and others included T3 and T4 tumors.9 These factors might influence the results of sentinel node biopsy, whether it is performed before or after chemotherapy.


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  		TABLE 3. Summary of studies with sentinel node biopsy performed after neoadjuvant chemotherapy: the false-negative rate was calculated if it was not provided in the text24
 
Several other explanations can be entertained for the poor results of lymphatic mapping specifically after neoadjuvant chemotherapy. The lymph flow pattern of the breast might be disturbed as a result of (shrinking) tumor or the chemotherapy per se.20 Another explanation could be that the odds of crossing a lymphatic watershed increase with an increasing tumor size, and drainage might occur to more than one node or more than one nodal basin. If the tumor shrinks, this watershed is crossed back again, and not all sentinel nodes of the (prechemotherapy) tumor will be visualized and pursued. This phenomenon is illustrated by the increased false-negative rate in patients with multifocal tumors.21–23 A last explanation may be that not all metastases react identically to chemotherapy. A metastasis in a sentinel node may disappear, but this does not necessarily mean that metastases in other axillary lymph nodes are equally responsive and thus also disappear.20

For all these reasons, none of the authors who published on sentinel lymph node biopsy after neoadjuvant chemotherapy has yet dared to abandon axillary lymph node dissection. The number of investigators who have performed sentinel node biopsy before neoadjuvant chemotherapy is limited (Table 4Go). Results of a total of 71 patients have been published with an identification rate of 100%. In this study and the study by Sabel et al.,34 it was deemed safe to abandon confirmatory lymph node dissection. To date, no axillary recurrences have been encountered in these patients (Sabel, personal communication, August 2005).


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  		TABLE 4. Summary of studies with sentinel node biopsy performed before neoadjuvant chemotherapy
 
Performing the procedure before neoadjuvant chemotherapy seems to be successful and safe so that axillary lymph node dissection can safely be omitted in some 56% of patients. This approach provides the advantages of neoadjuvant chemotherapy without the morbidity of axillary lymph node dissection in patients with uninvolved axillary lymph nodes.

Received for publication July 22, 2005. Accepted for publication October 27, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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