ORIGINAL ARTICLE. Therapeutic Effect of Sentinel Lymphadenectomy in T1 Breast Cancer

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1 ORIGINAL ARTICLE Therapeutic Effect of Sentinel Lymphadenectomy in T1 Breast Cancer David W. Ollila, MD; Meghan B. Brennan, RN, BSN; Armando E. Giuliano, MD Objective: To evaluate whether the tumor status of the sentinel lymph node (SN) would alter the systemic adjuvant therapy administered to patients with T1 breast cancer. Design and Patients: Consecutive breast cancer patients (tumors 2 cm) who underwent successful sentinel lymphadenectomy. Main Outcome Measures: Metastatic tumor in the SN, primary tumor size, recommendations for systemic adjuvant therapy before and after histopathologic evaluation of the SN, and actual systemic adjuvant therapy received by the patient. Results: Of 142 total patients, 14 had T1a tumors; 35, ; and 93,. Recommendations for systemic adjuvant therapy were initially determined solely by primary tumor characteristics and menopausal status. These recommendations were compared with recommendations for systemic adjuvant therapy based on tumor characteristics, menopausal status, and SN status; and then were compared with actual systemic adjuvant therapy received by the patient. Among the 118 patients with T1a,, and favorable (positive estrogen or progesterone receptors and a low S-phase percentage with respect to DNA content) tumors, 15 (37.5%) of 40 premenopausal patients and 20 (25.6%) of 78 postmenopausal patients became candidates for chemotherapy when examination of the SN revealed axillary metastasis; chemotherapy was actually administered to all 15 premenopausal patients but to only 6 postmenopausal patients. In the remaining 24 patients with unfavorable tumors, SN status did not change the recommendation for chemotherapy but may have altered the choice of specific chemotherapeutic agents. Conclusions: Identification of tumor-involved SN may alter systemic adjuvant therapy in patients with T1a,, and favorable tumors and may potentially change the type or dose of chemotherapeutic agents given to patients with unfavorable tumors. Surgical axillary staging of the axilla remains an essential part of breast cancer management and should not be abandoned. Arch Surg. 1998;133: From the John Wayne Cancer Institute at Saint John s Health Center, Santa Monica, Calif. FOLLOWING SURGICAL management of primary breast cancer, systemic adjuvant therapy is indicated for patients with axillary metastases but also is increasingly recommended for those without histological evidence of axillary node involvement. 1-3 Because of this trend to use systemic adjuvant therapy regardless of lymph node status and because of the direct relationship between the incidence of axillary metastasis and the size of the primary tumor, 4,5 recent reports have questioned the benefit of routine level I and II axillary lymph node dissection (ALND) in patients with T1 primary breast cancers, particularly T1a and lesions. 6,7 The National Institutes of Health Consensus Development Conference 8 on the treatment of early-stage breast cancer recommended levels I and II ALND for the prevention of axillary recurrence and for accurate staging. Axillary lymph node dissection improves regional control in patients with palpable 9,10 or nonpalpable 11 tumor-involved nodes, but its effect on survival remains controversial. It may prolong survival by removing metastatic disease or because more patients with lymph node metastases receive systemic adjuvant therapy. 12 However, patients without histologically involved nodes clearly do not derive a therapeutic benefit from ALND and must deal with the associated potential morbidity of the procedure Because routine ALND for all patients with T1 breast cancer is associated with potential morbidity and no realized therapeutic benefit in those without tumorinvolved lymph nodes, nonsurgical staging alternatives have been explored. Un- 647

2 PATIENTS AND METHODS Candidates for this study were patients undergoing operative management of potentially curable breast cancer at the John Wayne Cancer Institute from October 1,1991, through October 3,1995. Only clinically node-negative patients with histopathologically confirmed American Joint Committee on Cancer 24 T1 breast cancer were included. After signing informed consent forms, all patients underwent intraoperative lymphatic mapping with SLND, followed immediately by level I and II ALND. Patients who did not have a successful SLND were excluded. Our technique of intraoperative mapping and SLND for breast cancer has been described previously Each SN was examined by frozen and permanent section with hematoxylin-eosin staining. If no tumor was identified using hematoxylin-eosin, then a cytokeratin immunohistochemical stain was performed using an antibody cocktail (MAK-6, Ciba-Corning, Alameda, Calif) that binds to cytokeratins. The nonsentinel axillary lymph nodes were processed by routine surgical pathologic techniques for isolation of lymph nodes, and were examined only with hematoxylin-eosin. All patients were seen in consultation by at least 1 surgical oncologist (A.E.G.) and 1 medical oncologist. If a patient was ineligible or declined to participate in an adjuvant therapy trial, recommendations for systemic adjuvant therapy were made by the treating oncologist following the definitive breast cancer operation. For this study, we constructed an algorithm for determining systemic adjuvant therapy based solely on the patient s menopausal status and primary tumor characteristics (Figure). This algorithm was constructed from the following: University of California, Los Angeles Breast Center practice guidelines, 25 Eastern Cooperative Oncology Group (ECOG) Protocol 2188, recommendations from the National Institutes of Health Consensus Development Conference on the treatment of early-stage breast cancer, 8 results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-13, 26,27 and results from NS- ABP Protocol B The 1990 National Institutes of Health Consensus Development Conference recommended that women with T1a and tumors and no axillary metastases not receive systemic adjuvant therapy outside a clinical trial. 8 The NSABP Protocol B-14 reported a diseasefree survival advantage and a trend toward increased overall survival when women with tumor-negative axillary nodes and favorable primary tumors received tamoxifen treatment instead of placebo. 28 NSABP B-13 demonstrated a disease-free survival advantage and a trend toward increased overall survival following chemotherapy with methotrexate, fluorouracil, and leucovorin vs no chemotherapy in node-negative women with unfavorable tumors. 27 The recommendations derived from our primary tumor based systemic adjuvant treatment algorithm were then compared with SN-based systemic adjuvant treatment recommendations that included menopausal status, primary tumor characteristics, and tumor status of the SN. If the SN did not contain metastasis, the algorithm in the Figure was applicable. However, if the SN contained metastasis, chemotherapy was recommended for all premenopausal women and for all postmenopausal women without a prohibitive medical comorbidity. Finally, we compared algorithm-derived recommendations with the actual systemic adjuvant therapy received by the patient. fortunately, no radiographic technique possesses the sensitivity or specificity to be clinically reliable, 16 and none of the prognostic risk models based on clinical features and primary tumor characteristics have been validated in a prospective trial. The size of the primary tumor and the status of the axillary nodes remain the best predictors of survival. We previously reported the use of intraoperative lymphatic mapping, sentinel lymphadenectomy (SLND), and focused histopathological review of the SN for accurate staging of breast cancer. Given the recent trend to determine systemic adjuvant therapy without considering the tumor status of axillary lymph nodes, we examined whether the status of the SN is of practical value and alters the systemic adjuvant therapy for patients with T1 breast cancer. Our objective was to evaluate the clinical impact of a minimally invasive surgical axillary staging procedure on the systemic adjuvant therapy given to patients with T1 breast cancer. RESULTS The median age of the 142 patients eligible for study was 56.4 years (range, years). The size of the primary tumor as measured on histopathologic sectioning ranged from microinvasive (arbitrarily defined as 0.1 cm) to 2 cm in the greatest dimension (median, 1.15 cm). Following American Joint Committee on Cancer guidelines, 24 the distribution of tumors was 14 of type T1a ( 0.5 cm); 35, ( 0.5 cm but 1.0 cm); and 93, ( 1.0 cm but 2.0 cm). The histological status, hormonereceptor status, and flow cytometry results for the primary tumor are summarized in Table 1. Patients who had insufficient or inadequate tumor tissue for receptor assays or flow cytometry were considered to have favorable tumors. The mean number of SNs examined per patient was 1.8 (range, 1-7) (Table 2); the mean number of non-sns examined was 17.3 (range, 4-44). The use of both staining techniques identified 43 patients (30.3%) with SN metastases. Table 3 shows how recommendations for systemic adjuvant therapy changed with the identification of SN metastases. All 6 premenopausal women with T1a or tumors and SN metastases became candidates for and received systemic chemotherapy. All 9 premenopausal women with favorable lesions (positive for estrogen or progesterone receptors and a low S-phase percentage for DNA content) and SN metastases became candidates for and received systemic chemotherapy. Thus, 15 (37.5%) of the 40 premenopausal women with T1a,, or favorable tumors received a treatment they would not have received based only on primary tumor characteristics. Tumor involvement of the SN did not alter recommendation of chemotherapy as the adjuvant mo- 648

3 Premenopausal Patients T1 Breast Cancer Postmenopausal Patients Table 1. Primary Tumor Characteristics* Tumor Type T1a, No Treatment Favorable Hormonal Therapy Unfavorable Chemotherapy T1a, No Treatment dality for premenopausal patients with unfavorable tumors (negative for estrogen and progesterone receptors or an elevated S-phase percentage with respect to DNA content), but it may have altered the type or dose of chemotherapeutic agent in 6 (37.5%) of the 16 women. The 2 postmenopausal women with T1a or tumors and SN metastases were eligible for adjuvant chemotherapy but received tamoxifen. Eighteen postmenopausal women with favorable tumors and SN metastases were candidates for systemic adjuvant chemotherapy; however, only 6 patients actually received chemotherapy and the remaining 12 received tamoxifen. Thus, 20 (25.6%) of the 78 postmenopausal patients with T1a,, or favorable tumors were candidates for systemic adjuvant chemotherapy, but only 6 (30%) of the patients actually received the treatment while the others did not because of a preexisting prohibitive medical comorbidity, advanced patient age, or oncologist preference. The status of the SN did not alter therapeutic recommendations in postmenopausal women with unfavorable tumors. COMMENT Favorable Hormonal Therapy Unfavorable Chemotherapy Primary tumor based systemic adjuvant treatment algorithm. According to this treatment algorithm based on primary tumor characteristics, 8,25-28 patients with T1a and tumors would not receive systemic chemotherapy or hormonal therapy. Premenopausal women with favorable lesions (estrogen receptor positive or progesterone receptor positive, low S-phase percentage with respect to DNA content) would receive tamoxifen therapy, and premenopausal women with unfavorable tumors (estrogen receptor negative and progesterone receptor negative, high S-phase with respect to DNA content) would receive systemic adjuvant chemotherapy. Postmenopausal women with favorable cancers would receive tamoxifen therapy, whereas patients with unfavorable tumors would receive chemotherapy. Asterisk indicates If no prohibitive medical comorbidity exists. Cady et al 6 report a 13% incidence of axillary metastasis in patients with T1a and primary tumors and suggest that no axillary dissection is needed in patients with mammographically detected T1a or tumors. Silverstein et al 7 report only a 3% incidence of axillary metastases in T1a tumors and recommend no axillary dissection for patients with T1a tumors that demonstrate good prognostic features. However, review of the Surveillance, Epidemiology, and End Results (SEER) Program Registry 29 of more than 8000 T1 tumors shows a higher incidence of axillary metastasis: 19.6% for T1a tumors; 20.6%, ; and 33.1%,. Similarly, we previously reported a 15%, 15%, and 33% incidence of axillary metastases in T1a,, and tumors, respectively. 30 The SEER data and our own institutional data indicate that nonsurgical evaluation of the axilla T1a Total T1 (%) Median size, cm Histological finding Invasive ductal (87.3) Invasive lobular (9.2) Special subtypes (3.5) Receptor status Estrogen Positive (78.2) Negative (19.0) Insufficient material (2.8) Progesterone Positive (65.5) Negative (30.3) Insufficient material (4.2) DNA content Diploid (48.6) Aneuploid (40.9) Insufficient material (10.6) Proliferative index Low (57.0) High (21.8) Insufficient material (21.1) *Values are expressed as number of tumors with each characteristic, unless otherwise specified. Table 2. Results of Sentinel Lymphadenectomy* T1a (n = 14) Stage of Cancer (n = 35) (n = 93) Mean No. SNs examined (range) 1.6 (1-3) 1.7 (1-5) 1.8 (1-7) Tumor-positive SNs HE stain, No. of tumors detected Macrometastasis Micrometastasis IHC stain, No. of tumors detected *SN indicates sentinel node; HE, hematoxylin-eosin; IHC, cytokeratin immunohistochemical. would understage 15% to 20% of the patients with T1a or tumors. In the present study, tumor involvement of the SN had a significant effect on the recommendations for systemic adjuvant therapy administered to premenopausal patients with T1 breast cancers, compared with recommendations for systemic adjuvant therapy based on the primary tumor. Prior to SN examination, 40 patients (28.2%) would have received no systemic adjuvant treatment (for T1a or tumors) or adjuvant tamoxifen alone (for favorable tumors); detection of SN metastasis changed the recommendations for systemic adjuvant therapy in 15 (37.5%) of these patients. The potential benefit of systemic adjuvant chemotherapy is highest in premenopausal women with axillary metastases, 31 and accurate axillary staging is essential to avoid overtreatment (if the axilla is assumed to harbor metastasis) or undertreatment (if the nodes are assumed to be free of tumor). 649

4 Table 3. Systemic Adjuvant Therapy in 21 Premenopausal Patients and 22 Postmenopausal Patients With Sentinel Node Metastases Tumor-Based SN-Based Actual Tumor Type No. of Patients* C H C H C H Premenopausal Patients T1a 2/ (29) 0 2 (29) 0 4/ (36) 0 4 (36) 0 Favorable 9/ (41) 0 9 (41) 0 Unfavorable 6/ Postmenopausal Patients T1a 0/ / (8) (8) Favorable 18/ (39) 0 6 (13) 12 Unfavorable 2/ *Number of patients with sentinel node metastases/total number of patients. C indicates chemotherapy; H, hormonal. Systemic adjuvant therapy based solely on the primary tumor characteristics. Systemic adjuvant therapy based on primary tumor characteristics and tumor status of sentinel node. Systemic adjuvant therapy actually received by the patient. Values in parentheses indicate percent change from tumor-based systematic adjuvant therapy. Type of Adjuvant Therapy In our group of postmenopausal patients, 20 (25.6%) of 78 women with T1a,, or favorable tumors were candidates for systemic adjuvant chemotherapy based on metastatic tumor in the SN. The fact that only 6 (30.0%) of the 20 actually received chemotherapy underlines the tendency to avoid more aggressive systemic adjuvant therapy in postmenopausal women due to preexisting medical comorbidities, advanced chronologic and physiologic age, and/or oncologist preference. In our postmenopausal patients, controversy over the significance of axillary micrometastasis 32,33 detected by cytokeratin immunohistochemical staining may have discouraged more frequent use of adjuvant systemic chemotherapy. Patients with unfavorable tumors have a poorer prognosis than those with favorable tumors. The standard recommendation is systemic adjuvant chemotherapy regardless of lymph node status, providing there is no prohibitive medical comorbidity. The tumor status of the SN did not change recommendations for systemic adjuvant chemotherapy in this group of patients but it may have altered the selection of chemotherapeutic agents, particularly if completion ALND revealed multiple tumor-involved nodes. 34,35 Some medical oncologists might even consider high-dose chemotherapy with peripheral stem-cell support for patients with more than 10 involved nodes, 36 and some high-dose chemotherapy protocols are accepting patients with as few as 4 tumor-involved nodes. Thus, even patients with unfavorable tumors potentially could receive a different chemotherapy regimen based on identification of axillary metastasis. The clinical significance of axillary micrometastasis remains controversial, but the medical oncologists in our community consider micrometastatic SN involvement to be node-positive breast cancer. Thus, if the SN harbors tumor cells, all patients with T1a,, and favorable breast cancers potentially could receive an alternate systemic adjuvant therapy, whereas patients with unfavorable lesions might receive an alternate chemotherapeutic regimen. We recommend SLND to provide an axillary specimen for focused histopathologic examination. Except among those investigators who have demonstrated a high degree of accuracy with this technique, SLND should routinely be followed by completion level I and II ALND to ensure accurate axillary staging and effective regional control. Surgical staging of the axilla remains essential in the management of breast cancer and should not be abandoned. This study was supported by the Ben B. and Joyce E. Eisenberg Foundation, Los Angeles, Calif, and the Fashion Footwear Association of New York, NY. Presented at the 68th Annual Session of the Pacific Coast Surgical Association, Napa, Calif, February 16, Validating statistician for this study was Karen Qi, Statistical Coordinating Unit, John Wayne Cancer Institute. Reprints: Armando E. Giuliano, MD, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA REFERENCES 1. Mansour EG, Gray R, Shatila AH, et al. Efficacy of adjuvant chemotherapy in highrisk node-negative breast cancer. N Engl J Med. 1989;320: Fisher B, Redmond C, Wickerham L, et al. Systemic therapy in patients with nodenegative breast cancer. Ann Intern Med. 1989;111: Fisher B, Dignam J, Mamounas EP, et al. Sequential methotrexate and flu- 650

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