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ORIGINAL ARTICLES |
From the Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.
Correspondence: Address correspondence and reprint requests to: Mark C. Kelley, MD, Vanderbilt University Medical Center, 597 Preston Research Building, 21st Ave. South, Nashville, TN 37232-6860; Fax: 615-343-4598; E-mail: mark.kelley{at}mcmail.vanderbilt.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methods: A prospective clinical trial evaluated 122 patients who had SLND followed by axillary lymph node dissection. Thirty-two women had stage II or III breast cancer and received preoperative doxorubicin-based chemotherapy or paclitaxel and radiotherapy.
Results: A sentinel lymph node (SLN) was identified in 31 (97%) of 32 patients. The SLN predicted the status of the axillary nodes in 30 (97%) of 31 patients. Eighteen (58%) of 31 had metastases in the SLN. Eighteen of 19 patients with axillary metastases had a tumor-positive SLN (sensitivity, 95%; false-negative rate, 5%). Eight (44%) of 18 women with metastases in the SLN also had metastases in 1 or more nonsentinel nodes.
Conclusions: In this relatively small study, the accuracy of SLND in women with stage II or III breast cancer treated with preoperative therapy was similar to that achieved in early-stage breast cancer. If these results are confirmed in a larger cohort, it may be feasible to substitute SLND for routine axillary lymph node dissection in this population. This approach could reduce the morbidity of surgical therapy while preserving the accuracy of axillary staging and maintaining regional control in this high-risk population.
Key Words: Breast cancer • Lymphatic mapping • Sentinel lymph node dissection • Preoperative radiotherapy • Preoperative chemotherapy
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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SLND has been considered to be unreliable in certain subsets of patients, including those with locally advanced disease and those treated with preoperative therapy.12,13 Some have speculated that disruption of the lymphatic channels by tumor, inflammation, or fibrosis may impede the flow of radiolabeled colloid or dye.13 It has also been suggested that in patients treated with preoperative therapy, the cytotoxic effect on the tumor may be nonuniform, with preferential regression of metastatic disease in some axillary nodes, but not in others.13 These factors could lead to false-negative (FN) sentinel lymph nodes (SLN), inaccurate staging, and the possibility of undertreatment (e.g., omission of axillary dissection or postoperative adjuvant therapy).
To date, the results of studies evaluating the use of lymphatic mapping and SLND in patients treated with preoperative therapy have been conflicting. Nason et al.13 reported an FN rate of 33%. In contrast, others14–17 have reported FN rates of 0% to 12%, which are similar to those reported in patients who have not received preoperative treatment. We hypothesized that the staging accuracy of the lymphatic mapping and SLND might be compromised after preoperative therapy, leading to a low SLN identification rate and a high FN rate in this population. We addressed this question in patients with stage II or III breast cancer who received preoperative therapy and participated in a prospective clinical trial evaluating the accuracy of lymphatic mapping and SLND.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Of the 122 patients entered thus far, 50 (41%) had stage II or III disease according to the tumor-node-metastasis system of the American Joint Committee on Cancer. Thirty-two (64%) of these 50 received preoperative chemotherapy with or without radiotherapy. This subset of patients forms the basis for this report. All patients underwent a complete history and physical examination, bilateral mammograms, chest x-ray, complete blood count, liver function testing, and other radiological and laboratory studies as deemed clinically necessary. The diagnosis was established by fine-needle aspiration, core needle biopsy, or incisional or excisional biopsy, on the basis of clinical presentation. Fine-needle aspiration was performed on all patients with clinically positive axillary nodes, and a preoperative clinical stage was assigned on the basis of the results of this evaluation.
Preoperative Therapy
Of the 50 patients with stage II or III breast cancer, 32 underwent preoperative therapy, which included either doxorubicin-based chemotherapy off protocol (n = 25) or paclitaxel and concurrent radiotherapy (n = 7) on an institutional phase II clinical trial.18 Twenty-five patients received 5-fluorouracil, cyclophosphamide, and doxorubicin (FAC; n = 12) or doxorubicin and cyclophosphamide (AC; n = 13) therapy for four cycles. Seven patients received paclitaxel 175 mg/m2 intravenously every 3 weeks for three cycles, followed by concurrent paclitaxel (60 mg/m2 intravenously twice weekly for 6 weeks) and radiotherapy (46.8 Gy over 6 weeks to the whole breast and supraclavicular fossa).
Surgical Technique
Two to 4 weeks after the completion of preoperative therapy, patients were clinically re-staged and, where appropriate for tumor size, offered a breast-conserving procedure. All patients underwent SLND followed by standard ALND (level I and II). A total of 450 µCi of filtered 99mTc sulfur colloid was injected peritumorally 2 to 6 hours before surgery in all patients. The last 26 patients (of the 32 who received preoperative therapy) also received 300 µCi of filtered sulfur colloid intradermally over the primary lesion. Lymphoscintigraphy was performed in most patients. For patients with nonpalpable tumors, mammographic or ultrasound guidance was used for tumor localization. After the induction of anesthesia, 5 mL of 1% isosulfan blue dye was injected peritumorally, and the breast was massaged for 5 minutes. The axillary portion of the incision was then made, and the axilla was dissected bluntly to identify blue-stained lymphatics or nodes. A handheld gamma probe (Navigator; US Surgical Corp., Norwalk, CT) was used to localize nodes containing radioactive tracer, whether they were visually blue or not. All blue or significantly radioactive (
5 times the background in the nodal basin and/or 30 counts in vivo) nodes were excised and labeled as SLNs. If radioactivity in the axilla remained high (30 counts) after excision of the SLNs, the dissection continued, to find any additional SLNs. All palpable or clinically suggestive nodes were removed and labeled as non-SLNs unless they were significantly radioactive or blue. Patients then underwent the chosen surgical procedure for the primary lesion (total mastectomy or segmental resection) followed by level I and II ALND.
Pathology
Sentinel node and ALND specimens were submitted separately. All SLNs were evaluated with 1-mm serial sections and were stained with hematoxylin and eosin (H&E). Immunohistochemical staining with a monoclonal anticytokeratin antibody cocktail (AE-1/AE-3; Dako Corp., Carpinteria, CA) was used selectively at the pathologist’s discretion to clarify questionable areas identified on H&E staining. The remaining axillary nodes were evaluated with standard processing and H&E staining. Pathologic staging of the primary tumor and lymph nodes was performed according to American Joint Committee on Cancer criteria.19
Adjuvant Therapy, Follow-Up, and Statistical Analysis
The decision for adjuvant radiotherapy, hormonal therapy, or additional chemotherapy was individualized and was made by the medical oncologist in conjunction with the patient. In general, most patients who received AC or FAC before surgery received four cycles of paclitaxel followed by breast or chest wall radiotherapy. Patients who participated in the clinical trial evaluating preoperative paclitaxel received four cycles of AC after surgery. All women with hormone receptor–positive tumors received tamoxifen 20 mg daily by mouth for 5 years. Patients were evaluated every 3 to 4 months with physical examinations and yearly with mammography and laboratory or radiological studies as indicated on the basis of symptoms or physical examination findings. Local, regional, and systemic recurrence and survival were prospectively evaluated. The statistical significance of differences noted among subgroups of patients was evaluated with a two-tailed t-test with a power of .8 and a P value of .05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Lymphatic Mapping and Pathologic Results
An SLN was identified in 31 (97%) of 32 patients, with a mean of 2.5 SLNs (range, 1–6) identified per patient (Table 2). The SLN accurately predicted the axillary lymph node status of 30 (97%) of 31 of these women. Nineteen women had residual axillary metastases, and the SLN was involved in 18 (95%) of 19, indicating a sensitivity of 95% and an FN rate of 5%. Thirteen women had tumor-free SLNs, and only one had axillary nodal disease; this resulted in a negative predictive value of 92%. SLN status was also related to tumor size and nodal status before and after therapy, as well as clinical stage at presentation and pathologic stage after preoperative therapy (Table 3). Because there was only a single FN result, no correlation could be made between FN rate and these factors.
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In the entire study group, the SLN was identified in 113 (93%)of 122 patients. The status of the SLN predicted the axillary nodal status in 111 (98%) of these 113 patients. The FN rate for all 122 patients was 5% (2 of 43). For the 90 patients who did not receive preoperative therapy, the identification rate was 91% and the FN rate was 3%. The negative predictive value of the SLN in patients who did not receive preoperative chemotherapy was 95%. There were no statistically significant differences in SLN identification rate, FN rate, accuracy, or negative predictive value between the subgroups that did and did not receive preoperative therapy.
Follow-Up and Survival
At a median follow-up of 24 months, 28 (88%) of 32 women who received preoperative therapy were alive. Two of the 28 surviving patients have developed systemic recurrence and are currently receiving salvage therapy. No local or regional recurrences have been identified thus far, and no major complications were related to the lymphatic mapping procedure.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Few reports have evaluated the use of SLND in patients treated before surgery. In 1999, Nason et al.13 found a 33% FN rate among 15 patients. They suggested that preoperative therapy may impair the flow of radiocolloid or blue dye through tumor-laden lymphatics, distort patterns of lymphatic circulation, or cause regression of metastatic axillary disease in some nodes, but not in others. Our data suggest that these factors may not significantly affect the accuracy of SLND. One potential explanation for the discrepancy could be the fact that the studies by Nason et al. were performed earlier in the development of the lymphatic mapping technique, thus reflecting an earlier point in the learning curve. Our study was initiated in 1997, when there was no clinical experience with lymphatic mapping for breast cancer at our institution. More than half of the patients in this trial were accrued in the first 2 years of our experience. This suggests that our learning curve was included with these data and that differences in FN rates cannot be explained in this way. Nason et al. used a combination of intraparenchymal dye and colloid, similar to that used in our study. It is possible that the addition of intradermal colloid injection early in our study may have contributed to the lower FN rate we report. This is supported by several studies20,21 that show higher SLN identification rates and/or lower FN rates with intradermal versus intraparenchymal colloid injection.
Other studies have demonstrated that lymphatic mapping and SLND may be an accurate staging technique in breast cancer patients treated with preoperative therapy. This includes the largest single-institutional study by Breslin et al.,14 which showed an 84% identification rate and a 12% FN rate among 51 stage II and III patients who received preoperative therapy. These findings have also been confirmed by the National Surgical Adjuvant Breast and Bowel Program investigators, who reported an identification rate of 83% and an FN rate of 11% in patients participating in trials of preoperative chemotherapy.15 Julian et al.16 and Tafra et al.17 also documented SLN identification rates of 93% each and reported FN rates of 0% in small series of patients who had received preoperative therapy for breast cancer.
Preoperative chemotherapy provides several theoretical advantages to patients with stage II or III breast cancer. These include the reduction of local and regional tumor burden and early treatment of potential occult systemic disease. Although preoperative chemotherapy has not been shown to improve survival when compared with postoperative chemotherapy, the National Surgical Adjuvant Breast and Bowel Program B-18 trial showed that breast-conservation rates increased in patients treated with preoperative therapy.11,22 This is particularly true for patients with large T2 or T3 tumors, who may become candidates for segmental resection if a significant local tumor response can be achieved. In our series, 7 (78%) of 9 patients with large T2 lesions were downstaged to T1 or less, and 14 (88%) of 16 patients with T3 lesions were downstaged to T2 or less. Although none of the women in our study were considered to be candidates for breast conservation at presentation, 47% were able to undergo margin-negative segmental resection after preoperative therapy. The high breast-conservation rate achieved in this group of women with high local tumor burden supports the use of preoperative therapy. The absence of local failure is also encouraging, although a larger sample size and longer follow-up are needed before a definitive conclusion can be made regarding the results of breast conservation in this population.
It is interesting to note that there does not seem to be a strong correlation between response in the primary tumor and axillary lymph nodes. Four (67%) of six patients with complete regression of the primary tumor still had nodal metastases. Of the 14 patients with T3 lesions that were downsized, 10 (71%) had axillary metastases. Similarly, 50% of patients with tumors measuring <2 cm after preoperative therapy had axillary lymph node involvement. Our data also suggest that lymphatic mapping identified most nodes at risk for metastatic disease, because the SLNs were the only positive nodes in 56% of patients with axillary metastasis. Similar findings have been reported in other studies that investigated lymphatic mapping and SLND in early-stage breast cancer.2–7
The staging accuracy and low morbidity of lymphatic mapping and SLND has been demonstrated for several malignancies, particularly melanoma and breast cancer. SLND affords several advantages for breast cancer patients. It provides a minimally invasive procedure to detect nodal metastasis, thus defining a group of node-negative patients (42% in our study) who may be spared the morbidity associated with an ALND. SLND can improve the accuracy of staging by increasing the detection of micrometastatic disease in the SLN.2 Although detection of micrometastatic disease in the SLN is unlikely to alter therapy in most patients with stage II or III breast cancer, there are some scenarios in which this could be the case. For example, a patient with clinical stage IIa (T2N0) breast cancer treated with preoperative AC chemotherapy followed by segmental resection and SLND might not receive additional chemotherapy unless the SLN is involved with tumor.
In conclusion, lymphatic mapping and SLND accurately predicted the status of the axillary nodes in women with stage II and III breast cancer treated with preoperative therapy. The SLN identification rate, accuracy, and FN rate in this study are comparable to those reported in women with early-stage breast cancer who were not treated with preoperative therapy. Primary tumor size, clinical nodal status, clinical stage at presentation, or response to preoperative therapy did not correlate with staging accuracy or FN rate. It seems from the results of our own series and those published in the literature that a tumor-free SLN may be sufficient for staging the axilla in at least a subgroup of this population. Until a larger series confirms these results, a conservative approach is most appropriate, with routine ALND remaining the standard axillary staging procedure for women who have received preoperative therapy. Our findings warrant further evaluation of lymphatic mapping and SLND in this population, and we plan to continue to accrue patients onto this clinical trial. If these data are confirmed in a larger cohort, it may be possible to avoid axillary dissection in those with a tumor-free SLN. This could reduce the morbidity of surgical treatment while preserving staging accuracy in this group of women with high-risk breast cancer.
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FOOTNOTES |
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Received for publication May 10, 2002. Accepted for publication March 4, 2003.
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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