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Journal of Clinical Oncology, Vol 22, No 1 (January 1), 2004: pp. 97-101 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.108 Axillary Treatment in Conservative Management of Operable Breast Cancer: Dissection or Radiotherapy? Results of a Randomized Study With 15 Years of Follow-UpFrom the Departments of Surgery, Radiotherapy, and Biostatistics, Institut Curie, Paris, France Address reprint requests to K.B. Clough, MD, Service de Chirurgie, Institut Curie, 25 rue d'Ulm, 75 005 Paris, France; e-mail: christine.louissylvestre{at}chicreteil.fr
PURPOSE: Axillary dissection is the standard management of the axilla in invasive breast carcinoma. This surgery is responsible for functional sequelae and some options are considered, including axillary radiotherapy. In 1992, we published the initial results of a prospective randomized trial comparing lumpectomy plus axillary radiotherapy versus lumpectomy plus axillary dissection. We present an update of this study with a median follow-up of 180 months (range, 12 to 221 months). PATIENTS AND METHODS: Between 1982 and 1987, 658 patients with a breast carcinoma less than 3 cm in diameter and clinically uninvolved lymph nodes were randomly assigned to axillary dissection or axillary radiotherapy. All patients underwent wide excision of the tumor and breast irradiation. RESULTS: The two groups were similar for age, tumor-node-metastasis system stage, and presence of hormonal receptors; 21% of the patients in the axillary dissection group were node-positive. Our initial results showed an increased survival rate in the axillary dissection group at 5 years (P = .009). At 10 and 15 years, however, survival rates were identical in both groups (73.8% v 75.5% at 15 years). Recurrences in the axillary node were less frequent in the axillary dissection group at 15 years (1% v 3%; P = .04). There was no difference in recurrence rates in the breast or supraclavicular and distant metastases between the two groups. CONCLUSION: In early breast cancers with clinically uninvolved lymph nodes, our findings show that long-term survival does not differ after axillary radiotherapy and axillary dissection. The only difference is a better axillary control in the group with axillary dissection.
Standard management of the axilla in invasive breast carcinoma is axillary dissection, which provides both treatment and information on nodal status. Nonetheless, this procedure is responsible for functional sequelae, mainly arm edema. At present, the percentage of involved nodes is decreasing because diagnosis of breast cancer is made earlier, and the benefit of this surgery is in question. Some possible options are refraining from any axillary treatment in selected cases, sentinel node biopsy, or axillary radiotherapy. Axillary radiotherapy and axillary dissection were compared in only two randomized studies. The first is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B04 trial [1]. In this study, there was no difference in 10-year survival or in axillary failure rate between patients who received radical mastectomy (including axillary dissection) and patients who received total mastectomy (without axillary dissection) plus radiotherapy to the chest wall and regional lymph nodes. The other study is a prospective randomized trial conducted at the Institut Curie (Paris, France) between 1982 and 1987, comparing lumpectomy plus axillary dissection and lumpectomy plus radiotherapy of regional nodes. The 5-year results of this study were published in 1992 [2]. We observed a significant advantage for axillary dissection in overall and disease-free survivals. It was the only trial in the literature showing such a difference. We present an update of this study with a 15-year follow-up and provide elements to compare axillary radiotherapy and axillary dissection.
Patients and methods were extensively described in our article relating the 5-year results of this trial [2]. The main points are described in the following sections.
Inclusion
Treatments In group A, axillary dissection was limited to the nodes inferior to the axillary vein (level I and lower level II nodes). After axillary dissection, patients with metastatic nodes received radiation therapy to supraclavicular and internal mammary lymph nodes. In group A, patients with a tumor located in the central or medial part of the breast also received systematic radiation therapy to the internal mammary lymph nodes. In group B, no axillary dissection was performed. Irradiation to the breast was systematically associated with radiotherapy to axillary and internal mammary lymph nodes. All patients received radiotherapy to the breast at a dose of 55 Gy, fractionated over 6 weeks. All patients received a boost of 10 to 15 Gy to the tumor bed. Axillary nodes received a 50-Gy dose; internal mammary nodes and supraclavicular nodes received a 45-Gy dose. Some postmenopausal women with positive estrogen receptors were treated with tamoxifen 30 mg/d for 24 months, depending on their physician's choice, in accordance with 1982 policy. According to our protocols at that time, patients with more than one metastatic lymph node received adjuvant hormonal therapy or chemotherapy, depending on their menopausal status. In group A, 19 patients received cycles of cyclophosphamide 25 mg/m2, methotrexate 25 mg/m2, and fluorouracil 600 mg/m2 for 6 months. In group B, nine patients received the same regimen on the basis of age, tumor volume, and histologic grade.
Follow-Up
Statistical Analysis
Patients Between July 1982 and July 1987, 658 patients were entered onto the trial. There were 326 patients in group A and 332 patients in group B. Five-year results of this study were published in 1992 [2]. Mean age at randomization was 52 years in group A and 50.6 years in group B. Patient characteristics are presented in Table 1. Clinical presentation, histologic characteristics, and percentage of positive hormonal receptors were similar in the two groups. The only difference was the number of patients younger than age 35 years (nine in group A and 26 in group B).
Protocol Deviations Seven patients with axillary nodes (N1) suggestive of disease were enrolled even though they should not have been included in the protocol. Six of these patients were randomly assigned to group B and one patient was assigned to group A. The patient in group A and two patients in group B had an axillary dissection. All seven patients had chemotherapy or hormonal therapy. Three of these patients died as a result of metastases, one patient died at the age of 80 years, without evidence of disease, and the three remaining patients are alive with no evidence of disease. None of these seven patients developed a recurrence in the axillary region. The treatment protocol was not respected in 15 other patients. In group A, three patients had a mastectomy instead of a wide excision; six patients did not have axillary dissection and consequently received no treatment of the axilla. In group B, four patients had a mastectomy instead of a wide excision because of involved margins after the initial lumpectomy, and two N1 patients had an axillary dissection. All of these patients were maintained in their initial group and the analysis was conducted in an intention-to-treat fashion. Finally, 322 patients had an axillary dissection (320 in group A and two in group B). Among them, 68 had metastatic lymph nodes (21%): 39 patients (57%) had only one metastatic node, 23 patients (34%) had two or three metastatic nodes, and six patients (9%) had more than three metastatic nodes. Median follow-up was 180 months (range, 12 to 221 months). The outcomes at 60, 120, and 180 months are summarized in Table 2. Eleven patients were lost to follow-up at 5 years, and 58 patients were lost to follow-up at 10 years.
There is no statistical difference in overall survival or disease-free survival rates between the two groups in the long term (Figs 1 and 2; Table 2). Because our initial results published in 1992 showed a difference in overall survival in the short term, with a benefit for group A, we analyzed survival censoring the data at 60 months. The log-rank test applied for this 5-year period is still highly significant (P = .009) and confirmed the initial results (RR, 0.435; 95% CI, 0.240 to 0.790). This difference disappears at later evaluation. When disease-specific deaths were analyzed, there was no difference in the long term between the two groups.
Rates of ipsilateral breast recurrences were the same in the two groups at 60, 120, and 180 months (16.3% and 17.25%, respectively, at 180 months; Table 2). Rates of isolated axillary recurrences (without concomitant breast recurrence) were lower in group A at 60, 120, and 180 months: the rate was 1% in group A versus 3% in group B at 180 months (RR, 0.33; 95% CI, 0.11 to 0.98; P = .04; Table 2; Fig 3). Seventeen patients developed an axillary recurrence (five in group A and 12 in group B). Five of these patients had a concomitant breast recurrence. Among the 12 patients without a concomitant breast recurrence, three were in group A and nine were in group B. Eight of these patients later developed metastases. Only one patient with a metastatic lymph node on initial axillary dissection developed an axillary recurrence during the follow-up.
Rates of distant metastases or supraclavicular node involvement were the same in the two groups (24.9% and 25.8%, respectively) at 180 months (Table 2).
When we published the 5-year results of this randomized study, we observed an improved survival rate with axillary dissection compared with axillary radiation therapy in conservative treatment of breast cancer [2]. Our recent findings with a longer follow-up show that long-term survival at 10 and 15 years and metastases rates are identical in both groups. The only difference that remains in the long term between the two groups is a lower rate of axillary recurrences after axillary dissection (RR, 0.33; P = .04). The NSABP B04 trial is the only other randomized study testing the difference in outcome between axillary radiotherapy and axillary dissection. In this study, patients were treated with radical mastectomy and axillary dissection, mastectomy and radiotherapy to the chest wall and the lymph nodes, or mastectomy alone. Ten-year overall survival and disease-free survival rates were the same in the first two arms [1]. With longer follow-up, the present conclusions of our study now match those of the NSABP B04 trial on survival. It is possible that the difference of survival we observed with a 5-year follow-up was because more patients in group A were treated with adjuvant chemotherapy. Nine patients in group B received chemotherapy (on the basis of age, tumor size, and grade), whereas 19 in group A were treated because of known positive lymph nodes. This overtreatment in group A compared with group B could be responsible for the improved survival in the short term, as published in 1992 [2]. The only difference that remains between the two treatments at 15 years is a higher rate of isolated axillary recurrences with radiotherapy (3% v 1%). This 3% recurrence rate is consistent with the rates published by Recht et al [3] in their review about axillary treatments. It is worth noting that our study took place in the 1980s. It is possible that technical improvements of modern radiotherapy, including the use of better imaging and dosimetric systems, might lead to a smaller figure. In prospective studies it was demonstrated that isolated axillary recurrences in the nontreated axilla might not alter outcome [1,4]. Conversely, retrospective studies showed that recurrences in the treated axilla worsen the prognosis [3,5,6]. Nonetheless, the number of patients who developed an axillary recurrence after treatment in our series is too small to modify overall survival in group B. Given that late survival rates are identical in the two arms, the comparison of respective benefits of these two treatments has to rely on other criteria. Data on specific morbidity of each treatment were not prospectively recorded in our study. Analysis of the literature shows that rates of complications of the two treatments seem to be in the same range [7-9]. Axillary node dissection is responsible for lymphedema of the arm and restriction of shoulder motion in 10% to 20% of the patients [7,8]. The objective arm edema rate is reported to be approximately 10% after axillary radiotherapy, whereas impairment in shoulder function is approximately 17% [9]. The major advantage of axillary dissection is to provide information on nodal status, and this is used to determine whether adjuvant therapy is indicated. However, indications for chemotherapy have widened over the years, and rely less on nodal status alone. The tumor features may provide enough information to evaluate the risk of metastases and allow the clinician to decide whether systemic adjuvant therapy is necessary. Nonetheless, positive nodes remain a major prognostic factor in all multivariate studies. In the future, node assessment might remain necessary to lead to more targeted treatments. In this setting, the sentinel node biopsy could provide the information without the functional price of complete axillary dissection. However, identification of the sentinel node is not yet recognized as the standard of care [10], and several randomized studies are currently comparing sentinel node biopsy and complete axillary dissection. It already has been demonstrated that, in experienced hands, sentinel node biopsy is reliable, with a false-negative rate of less than 5% [11-13]. In some teams, sentinel node biopsy has become part of the routine protocol for management of selected patients. Recently, a consensus conference established the use of this technique for N0, M0 tumors less than 30 mm [14]. In these early breast cancers, we face the problem of the treatment of the axilla in patients with a positive sentinel node. The standard is completion of axillary dissection. Some authors are in favor of no additional treatment in selected patients [15]. This option is currently being evaluated in a randomized trial of the American College of Surgical Oncology comparing axillary dissection with abstention. Axillary radiotherapy of the axilla might be another option, and it is currently being evaluated in a randomized trial of the European Organization for Research and Treatment in Cancer comparing axillary radiotherapy versus axillary dissection in patients with a positive sentinel node. Our study demonstrates, with a 15-year follow-up, that axillary dissection and axillary radiotherapy provide identical survival, although local control is better with axillary dissection. The morbidity of the association between sentinel node biopsy and subsequent axillary radiotherapy remains to be evaluated.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Fisher B, Redmond C, Fisher ER, et al: Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 312:674-681, 1985[Abstract] 2. Cabanes PA, Salmon RJ, Vilcocq JR, et al: Value of axillary dissection in addition to lumpectomy and radiotherapy in early breast cancer. Lancet 339:1245-1248, 1992[CrossRef][Medline] 3. Recht A, Pierce SM, Abner A, et al: Regional nodal failure after conservative surgery and radiotherapy for early-stage breast cancer. J Clin Oncol 9:988-996, 1991[Abstract] 4. Greco M, Agresti R, Cascinelli N, et al: Breast cancer patients treated without axillary surgery. Ann Surg 232:1-7, 2000[CrossRef][Medline] 5. Renolleau C, Merviel P, Clough KB, et al: Isolated axillary recurrences after conservative treatment of breast cancer. Eur J Cancer 32A:617-621, 1996 6. Fowble B, Solin LJ, Schutz DJ, et al: Frequency, sites of relapse, and outcome of regional node failure following conservative surgery and radiation for early breast cancer. Int J Radiat Oncol Biol Phys 17:703-710, 1989[Medline]
7. Lin PP, Allison DC, Wainstock J, et al: Impact of axillary lymph node dissection on the therapy of breast cancer patients. J Clin Oncol 11:1536-1544, 1993 8. Roses DF, Brooks AD, Harris MN, et al: Complications of level I and II axillary dissection in the treatment of carcinoma of the breast. Ann Surg 230:194-201, 1999[CrossRef][Medline] 9. Hoebers FJP, Borger JH, Hart AAM, et al: Primary axillary radiotherapy as axillary treatment in breast-conserving therapy for patients with breast carcinoma and clinically negative axillary lymph nodes. Cancer 88:1633-1642, 2000[CrossRef][Medline]
10. Krag D, Weaver D, Ashikaga T, et al: The sentinel lymph node in breast cancer: A multicenter validation study. N Engl J Med 339:941-946, 1998 11. Giuliano AE, Kirgan DM, Guenther JM, et al: Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg 220:391-398, 1994[Medline] 12. Veronesi U, Paganelli G, Galimberti V, et al: Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet 349:1864-1867, 1997[CrossRef][Medline]
13. Nos C, Freneaux P, Guilbert S, et al: Sentinel node detection for breast cancer: Which patients are best suited for the patent blue dye only method of identification?. Ann Surg Oncol 8:438-443, 2001 14. Schwartz GF, Giulano AE, Veronesi U: The Consensus Conference Committee: Proceeding of the consensus conference of the role of the sentinel node biopsy in carcinoma of the breast April 19-22, 2001, Philadelphia PA, USA. Breast J 8:124-138, 2002[Medline] 15. Cady B: A contemporary view of axillary dissection. Ann Surg 232:8-9, 2000[CrossRef][Medline] Submitted December 17, 2002; accepted October 21, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
