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Originally published as JCO Early Release 10.1200/JCO.2005.01.5784 on December 12 2005 © 2006 American Society of Clinical Oncology. Randomized Trial Comparing Axillary Clearance Versus No Axillary Clearance in Older Patients With Breast Cancer: First Results of International Breast Cancer Study Group Trial 10-93International Breast Cancer Study GroupAddress reprint requests to Carl-Magnus Rudenstam, MD, West Swedish Breast Cancer Study Group, Sahlgrenska University Hospital/Mölndal, Göteborgsvägen 31, 431 80 Mölndal, Sweden; e-mail: c-m.rudenstam{at}telia.com
Purpose: Axillary clearance in early breast cancer aims to improve locoregional control and provide staging information but is associated with undesirable morbidity. We therefore investigated whether avoiding axillary surgery in older women would result in improved quality of life (QL) with similar disease-free survival (DFS) and overall survival (OS).
Patients and Methods: Between 1993 and 2002, women Results: A total of 473 patients (234 to Sx + Ax, 239 to Sx) were randomly assigned. The median age was 74 years; 80% had estrogen receptor–positive disease. In both the patients' subjective assessment of their QL and the physicians' perception of the patients' QL, the largest adverse QL effects of Ax were observed from baseline to the first postoperative assessment, but the differences tended to disappear in 6 to 12 months. At a median follow-up of 6.6 years, results for Sx + Ax and Sx yielded similar DFS (6-year DFS, 67% v 66%; hazard ratio [HR] Sx + Ax/Sx, 1.06; 95% CI, 0.79 to 1.42; P = .69) and OS (6-year OS, 75% v 73%; HR Sx + Ax/Sx, 1.05; 95% CI, 0.76 to 1.46; P = .77).
Conclusion: Avoiding axillary clearance for women
The incidence of breast cancer increases with age1 and breast cancer is the most common cancer in women older than 70 years old.2 In Western countries, approximately 50% of women with breast cancer are older than 65 years old. Given that populations are aging, increasing numbers of breast cancer occurrences can be expected among older women. Comorbid conditions also increase with age.3 Because these conditions may limit the duration and extent of a surgical procedure, there is a potential advantage to avoiding axillary surgery if it does not compromise tumor control. Avoiding axillary surgery might also reduce postoperative effects on arm pain, mobility, and lymphedema. Recent data4,5 suggest that there is an association between increasing age at diagnosis and the presence of more favorable biologic characteristics of the tumor, such as greater expression of steroid hormone receptors, lower proliferative rates, diploidy, normal p53 expression, and the absence of overexpression of epidermal growth factor receptor and c-erbB-2. We therefore investigated whether older patients with clinically node-negative and primarily endocrine-responsive early breast cancer might benefit from a change to the surgical approach that eliminates axillary lymph node dissection. This surgery usually represents the main cause of morbidity after a breast cancer resection, especially because such patients would receive adjuvant treatment with tamoxifen. Our study compares older patients undergoing breast surgery treated with axillary surgery versus patients who received no axillary surgery to determine the effect of axillary surgery on quality of life (QL), disease-free survival (DFS), and overall survival (OS).
Study Design From May 1993 through December 2002, 473 postmenopausal patients 60 years or older with clinically node-negative operable breast cancer were randomly assigned preoperatively to receive breast surgery with axillary clearance followed by tamoxifen (20 mg) for 5 years or breast surgery without axillary clearance followed by tamoxifen (20 mg) for 5 years. At the time of random assignment, estrogen receptor (ER) status and pathologic nodal status were unknown. Informed consent was required according to the criteria established within the individual countries. The protocol was reviewed and approved by institutional review boards. Random assignment was performed centrally (at the coordinating centers in Bern, Switzerland, or Sydney, Australia) after stratification according to whether primary surgery was performed before random assignment (yes or no), age (60 to 70 or > 70 years), and by participating institution. The permuted-blocks randomization schedule was produced by use of pseudorandom numbers generated by a congruence method.
All patients had a histologically proven unilateral breast cancer of stage T1a, T1b, T2a, T2b, T3, N0, or M0 (Union Internationale Contre le Cancer 1987), with either ER-positive or ER-negative primary tumors. Steroid hormone receptor concentrations in the primary tumors were determined by standard methods. ER concentrations of In August 2002, the International Breast Cancer Study Group (IBCSG) Scientific Committee made a recommendation to discontinue tamoxifen for patients with endocrine-nonresponsive tumors. Surgery to remove the primary tumor was either a total mastectomy or breast-conserving surgery. On April 15, 1999, the original protocol was amended to allow institutions to perform sentinel node biopsy (SNB) in patients who had been randomly assigned to surgery, provided they then proceeded to axillary clearance. However, only two patients used this option. Radiotherapy using two tangential fields was recommended after breast-conserving surgery. Clinical, hematologic, and biochemical assessments were required every 3 months for the first year, every 6 months during years 2 through 5, and yearly thereafter. Modified WHO toxicity grading criteria were used. Yearly mammography was optional. The data management and medical staff reviewed all study records (initial data, treatment, toxicity, and recurrence) and conducted regular site visit audits. In particular, the study chairs (D.C. and C-M.R.) reviewed the records of all patients for eligibility and adverse effects. Patient self-assessments of QL using the IBCSG approach6-9 were obtained before surgical treatment; postoperatively; at months 3, 6, 9, 12, 18, and 24; and yearly thereafter for 6 years. Single-item linear analog self-assessment scales that were scored between 0 and 100 were used; higher values represented better QL or less severe symptoms. The QL form consisted of a one-page core questionnaire8 and a surgical QL module specific to this trial. Four scales on the core questionnaire were used from the start of the trial to measure physical well-being, mood, appetite, and perceived adjustment/coping. After May 1, 1993, six additional linear analog self-assessment scales were added to the core questionnaire to measure tiredness, hot flashes, nausea/vomiting, perceived social support, arm restriction, and subjective health estimation. The surgical QL module was first introduced on July 1, 1995, to measure swelling, numbness, weakness, pain, stiffness, performance of daily activities compared with the time before surgery, and a global measure of being bothered by any problems with hand, arm, shoulder, or chest.6 We expected the latter to be less precise for specific effects but responsive to the whole spectrum of sequelae and selected it as the primary end point. QL scores were transformed to reduce skewing, and the statistical significance of treatment differences at each time point was assessed with analysis of variance, adjusting for country/language group.7,8 Physician assessments of the patients' QL were collected at the beginning of treatment; at first follow-up after discharge from final surgery; and at months 3, 6, 9, 12, 18, and 24. QL measures assessed by the physician included ipsilateral arm movement; arm, shoulder, and chest wall pain; arm circumference; and performance of daily activities with respect to preoperative levels.
End Points and Statistical Considerations DFS and OS percentages, SEs, and treatment effect comparisons were obtained from the Kaplan-Meier method,10 Greenwood's formula,11 and log-rank tests,12 respectively. Cox proportional hazards regression models13 were used to estimate relative risks and 95% CIs for the treatment comparisons. Cumulative incidence of breast-related events is reported with nonbreast cancer events (ie, nonbreast second primary cancer or death without prior recurrence) as competing risks.14 Classification according to nodal status was not used in a primary analysis because the opportunity to determine nodal status depended on the randomization option. All probability values were obtained from two-sided tests. Results are reported at a median follow-up of 6.6 years. The trial was originally designed to assess equivalence between the axillary clearance and no axillary clearance treatment groups in terms of DFS. Using a one-sided .05-level test, a sample size of 1,020 patients (or 455 events) would provide 90% power to reject the hypothesis of equal treatment effectiveness. As of August 3, 2000, accrual was 430 patients. On the basis of the yearly accrual rate, it would have taken more than 20 additional years of accrual to reach the target sample size of 1,020 patients. On November 2, 2000, the study was redesigned to assess whether avoiding axillary clearance improved QL results. For consideration of sample size, we focused on one question from the surgical QL module assessed at 24 months: "Overall, how much are you bothered by any problems with your hand, arm, shoulder, or chest?" To detect a decrease of 13% in the percentage of patients bothered by hand, arm, shoulder, or chest (defined as a score of 85 or less) for patients not receiving axillary clearance with 80% power required a total of 472 randomly assigned patients. The Wilcoxon rank sum test15 was used for testing differences between continuous variables, and associations between categoric variables were assessed by a Fisher's exact test.16 The Data and Safety Monitoring Committee reviewed accrual and safety data twice a year. The original study plan called for an interim analysis after 112 DFS events or 25 axillary recurrences had been observed. The first interim analysis took place after the last patient was enrolled.
Patient Eligibility and Characteristics Of the 473 patients randomly assigned, 19 patients (4%) did not meet protocol eligibility criteria for the following reasons: incorrect stage (n = 9: five T4, three in situ only, one bone metastasis), prior or concurrent malignancy (n = 6), non-Hodgkin's lymphoma (n = 1), did not have breast cancer (n = 1), medically unsuitable (n = 1), and treatment started before random assignment (n = 1). However, all 19 ineligible patients are included in the intent-to-treat analyses. The characteristics of the 473 patients are shown in Table 1. Baseline characteristics were balanced according to randomly assigned treatment arm. The median age was 74 years in both randomly assigned treatment groups. Twenty-two percent of the patients had received prior hormone replacement therapy and 80% of the patients had primary tumors classified as ER positive. Twenty-eight percent of the patients who had axillary clearance were found to have involved nodes. The median number of examined lymph nodes was 13. Forty-five percent of the patients were treated with mastectomy, 33% had breast-conserving surgery with radiotherapy, and 23% had breast-conserving surgery without radiotherapy.
QL Physicians were asked whether the patient experienced restricted ipsilateral arm movement and whether the patient experienced arm pain. For both end points, we found a statistically significant increase in physician-reported adverse effects in the first postoperative period for patients who had an axillary clearance. At the first postoperative assessment, there was a statistically significant increase in the restriction of arm movement in the group that received axillary clearance (39% v 15% in the group with no axillary clearance; P = .000001; Fig 1A). However, after the immediate postoperative period, the percentage of patients for whom the physicians reported restricted arm movement approached the preoperative values in both groups. Similar results were observed for physician-reported arm pain. For this end point physicians reported 23% of patients with arm pain among those receiving axillary clearance versus 7% in the other group at the first postoperative assessment (P = .00006; Fig 1B). This difference between treatments was no longer statistically significant at later follow-up assessments. The two other physician-reported QL end points, arm circumference and performance of daily activities, were not significantly different between treatments. The proportion of patients that developed lymphedema, defined as a 5% or greater increase in arm circumference from baseline, was also not significantly different between treatments.
Patient self-assessment of QL was available for 394 patients for the core questionnaire and 257 assessable patients for the study-specific module. For the protocol-specific question about being bothered by hand, arm, shoulder, or chest problems, patient responses showed similar differences between the two treatments as the evaluation performed by the physicians (Fig 2A). The largest difference was observed from baseline to the first postoperative assessment (P = .01), and there was a return to baseline levels over time. Other surgery-related symptoms assessed by the patient included restriction in arm movement and numbness. At the first postoperative assessment, patients in the group with axillary clearance reported more restriction in the use of their arm (Fig 2B; P < .0001) and more severe postsurgery numbness (Fig 2C; P = .04). For those measures not specifically related to surgery sequelae, no significant differences were observed at any of the time points. In addition, patients reported similar efforts to cope with their disease regardless of treatment assignment (Fig 2D).
DFS and OS Overall, the two treatment groups were similar with respect to both DFS (6-year DFS = 67% with axillary clearance v 66% without axillary clearance; HR = 1.06; 95% CI, 0.79 to 1.42; P = .69; Fig 3A) and overall survival (6-year OS = 75% with axillary clearance v 73% without axillary clearance; HR = 1.05; 95% CI, 0.76 to 1.46; P = .77; Fig 3B). Within the ER-positive cohort the two treatment groups were similar with respect to both DFS (6-year DFS = 68% with axillary clearance [n = 179] v 66% without axillary clearance [n = 201]; HR = 1.01; 95% CI, 0.72 to 1.41; P = .95) and OS (6-year OS = 76% with axillary clearance [n = 179] v 74% without axillary clearance [n = 201]; HR = 0.97; 95% CI, 0.66 to 1.42; P = .87). Similarly, no treatment difference was observed for the ER-negative cohort for DFS (6-year DFS = 62% with axillary clearance [n = 46] v 64% without axillary clearance [n = 31]; HR = 1.35; 95% CI, 0.68 to 2.65; P = .39) and OS (6-year OS = 68% with axillary clearance [n = 46] v 69% without axillary clearance [n = 31]; HR = 1.51; 95% CI, 0.72 to 3.17; P = .28).
Sites of First Event Sites of first event were similar between the two treatment groups (Table 2). We observed only a 2% incidence of axillary recurrence overall (as first event) and no statistically significant difference between the two treatment options. One patient, who did not receive an axillary clearance, experienced a subsequent axillary recurrence. All of the patients who had an axillary recurrence received a late axillary clearance after recurrence. Seventeen percent of the patients experienced a breast cancer–related recurrence, whereas 21% experienced a nonbreast second primary cancer or death without recurrence. Because a high percentage of patients had competing events related to nonbreast cancer, we examined the cumulative incidence of breast and nonbreast cancer events by treatment. No differences were observed according to treatment group (Fig 4).
Tamoxifen Treatment and Toxicity At the time of this report, 185 patients (39%) had completed 5 years of tamoxifen and 16 patients (3%) received no tamoxifen (six with ER-positive tumors; five with ER-negative tumors; five with ER status unknown). Reasons for not receiving tamoxifen included recurrence (n = 4), patient refusal (n = 2), no invasive breast cancer (n = 4), clinical decision (n = 5), and early death (n = 1). Grade 3 or worse toxicities were experienced by 7% of patients during the tamoxifen therapy (7% with axillary clearance and 8% without axillary clearance). Grade 3 or worse toxicities that were observed included mostly thromboembolic events and cerebral vascular toxicities.
The morbidity of axillary dissection has led some investigators to question its necessity,17 whereas others have studied alternatives such as axillary radiation therapy18 and SNB.19,20 This randomized study examines the option of avoiding axillary surgery altogether and shows that in older women with clinically negative axillary examination, this transiently improves QL (mainly during the first year as assessed by both patients and their physicians) apparently without compromising DFS or OS results. The median age of the patients enrolled onto IBCSG Trial 10-93 was 74 years, which is substantially older than the median age in most adjuvant therapy trials conducted for postmenopausal patients. QL measurements by both physician and patient showed significantly inferior arm-related QL scores after axillary surgery. A similar comparison of arm-related complaints by Veronesi et al21 showed similar but larger differences between complete axillary surgery and SNB in women of all ages. The trial was originally designed to assess equivalence between the axillary clearance and no axillary clearance treatment groups in terms of DFS and OS, but the accrual was slower than anticipated; the primary goal shifted to assessing the QL end point. Therefore, the study was not powered to establish treatment equivalence. However, based on our current results, a predictive power calculation indicates that the chance that a fully accrued trial would have found a statistically significant benefit in DFS for patients who received axillary clearance was less than 3%. We conclude that axillary clearance does not contribute greatly to DFS or OS.22 Nevertheless, no obvious differences were observed in DFS or OS up to 6.6 years of median follow-up. Regional recurrence or reappearance of disease in the axilla was observed for only 2% of the patients overall (3% without axillary clearance and 1% with axillary clearance). Results of our earlier IBCSG Trial IV (patients 66 to 80 years old at random assignment) demonstrated that adjuvant tamoxifen plus low-dose prednisone administered for 1 year provided significant improvement in DFS and OS (evident principally in improved locoregional control) compared with no adjuvant therapy for elderly patients with more than 20 years of follow-up,23 although at present, we consider 1 year of tamoxifen a suboptimal duration of this therapy. Thus, we deduce that 5 years of tamoxifen included in this study may have prevented at least some axillary recurrences. Given the postoperative morbidity and the decrease in QL associated with axillary surgery, especially for this elderly population, the trial results provide important evidence to support the option of avoiding axillary clearance. Maunsell et al24 studied the frequency of reported arm problems and described that 3 months postsurgery, as much as 82% of the patients (n = 223) reported at least one arm problem, the most frequent being numbness (54%) and pain (55%); at the 18-month assessment, the percentage of patients reporting at least one problem remained almost unchanged (79%). Eighty percent of the women enrolled onto our study had tumors that were classified as ER positive, and 96% of all patients received at least some tamoxifen as adjuvant therapy. This high proportion of patients with an endocrine-responsive disease who received an effective adjuvant endocrine treatment must be taken into account when interpreting the results of the trial. A recent randomized study conducted by the Cancer and Leukemia Group B (CALGB) investigators25 evaluated the role of radiotherapy in older women with clinical stage I (T1, N0, M0) and ER-positive breast carcinoma treated with lumpectomy and tamoxifen for 5 years. In the CALGB trial, the axillary node dissection was allowed but discouraged, confirming our hypothesis that this approach is common in clinical practice in populations of women older than 70 years. In the CALGB trial, only two isolated axillary recurrences were found in women treated with lumpectomy and tamoxifen. Conversely, avoiding axillary clearance for older women with ER-negative tumors may not be as safe, as suggested by the overall outcomes reported in our study. It may be argued that axillary surgery might still be worthwhile to determine whether to offer chemotherapy to these patients. Although knowing the axillary nodal status may be necessary to choose the best adjuvant systemic therapy, it is less relevant in an elderly population at low risk and with an inherently shorter life expectancy. Thus, the recent trend to substitute SNB can also be called into question, given that our present results seem to support avoidance of axillary dissection. 25 This line of reasoning is based on the older supposition that chemotherapy should be used for older patients with node-positive disease, but not for patients with node-negative disease. More recently, the endocrine responsiveness of the primary tumor, not the nodal status, is the relevant feature used for guidance in the decision whether to use chemotherapy.26 Data for the 50- to 69-year age group from the Early Breast Cancer Trialists’ Collaborative Group Overview27 demonstrate that for patients with endocrine-responsive disease, endocrine therapy (specifically tamoxifen) provides the majority of the advantage associated with adjuvant treatments. Thus, because nodal status is less relevant for determining whether chemotherapy is indicated, there may be no need to perform even SNB procedures for an older woman with endocrine-responsive and clinically node-negative disease. For older women who do require axillary dissection either because of clinical node involvement or because of a positive SNB, the results of this study are reassuring, demonstrating that for most of these women, there is little effect from this surgery on their long-term daily functioning or their QL. Younger women reported higher rates of arm morbidity than older women, perhaps because these symptoms have a greater impact on their functioning.28 In a recent study assessing long-term morbidity after axillary surgery for breast cancer, Taylor29 reported that three fourths of 208 patients had at least one long-term symptom (3 to 6 years). Similar findings were reported by another group,30 supporting the need to study less invasive procedures at least for clinically node-negative patients. Although several studies have specifically compared arm morbidity between women undergoing standard axillary clearance and those receiving SNB,19-21,31,32 these have not focused on the elderly patient population. In summary, IBCSG Trial 10-93 has demonstrated that avoiding axillary clearance for older women with clinically node-negative breast cancer who receive adjuvant tamoxifen seems safe and results in early improved QL for this older population of patients. These results apply primarily for patients with endocrine-responsive disease in whom the use of tamoxifen is associated with substantial benefit in terms of disease control. For older women with endocrine-nonresponsive disease, the tailored use of adjuvant systemic chemotherapy is being investigated in an ongoing randomized clinical trial (Chemotherapy Adjuvant Study for Women at Advanced Age: CASA), coordinated by the IBCSG on behalf of the Breast International Group.
The authors indicated no potential conflicts of interest.
We thank the patients, physicians, nurses, and data managers who participate in the International Breast Cancer Study Group trials. We thank Rita Hinkle for central data management and Robert Gray for statistical advice.
From the International Breast Cancer Study Group. Appendix lists the names and affiliations of the writing committee, and participants and authors of Trial 10-93 Supported in part by the Swiss Group for Clinical Cancer Research, Frontier Science and Technology Research Foundation, The Cancer Council Australia, Australian New Zealand Breast Cancer Trials Group (National Health Medical Research Council), National Cancer Institute (Grant No. CA-75362), Swedish Cancer Society, Cancer Association of South Africa, and Foundation for Clinical Research of Eastern Switzerland. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Schrenk P, Rieger R, Shamiyeh A, et al: Morbidity following sentinel lymph node biopsy versus axillary lymph node dissection for patients with breast carcinoma. Cancer 88:608-614, 2000[CrossRef][Medline] 20. Burak WE, Hollenbeck ST, Zervos EE: Sentinel lymph node biopsy results in less postoperative morbidity compared with axillary lymph node dissection for breast cancer. Am J Surg 183:23-27, 2002[CrossRef][Medline] 21. Veronesi U, Paganelli G, Viale G, et al: A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 349:546-553, 2003 22. Jennison C, Turnbull BW: Statistical approaches to interim monitoring of medical trials: A review and commentary. Stat Sci 5:299-317, 1990[CrossRef] 23. Crivellari D, Price K, Gelber RD, et al: Adjuvant endocrine therapy compared with no systemic therapy for elderly women with early breast cancer: 21-year results of International Breast Cancer Study Group Trial IV. 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Peintinger F, Reitsamer R, Stranzl H, et al: Comparison of quality of life and arm complaints after axillary lymph node dissection vs sentinel lymph node biopsy in breast cancer patients. Br J Cancer 89:648-652, 2003[CrossRef][Medline] Submitted February 14, 2005; accepted June 13, 2005. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
60 years old with clinically node-negative operable breast cancer in whom adjuvant tamoxifen was considered indicated regardless of pathologic nodal status were randomly assigned to primary surgery plus axillary clearance (Sx + Ax) followed by tamoxifen (Tam) versus Sx without Ax followed by Tam for 5 consecutive years. The primary end point was QL reported by the patient and by physician assessment. 
