Randomized Trial Comparing Axillary Clearance vs No Axillary Clearance in Older Patients With Breast Cancer

Abstract & Commentary

By Stuart M. Lichtman, MD, Associate Attending, Memorial Sloan-Kettering Cancer Center, Commack, NY. Dr. Lichtman reports no financial relationship to this field of study.

Synopsis: Avoiding axillary clearance for women 60 years of age and older who have clinically node-negative disease and receive Tam for endocrine-responsive disease yields similar efficacy with better early QoL.

Source: International Breast Cancer Study Group. Randomized Trial Comparing Axillary Clearance Versus No Axillary Clearance in Older Patients with Breast Cancer: First Results of International Breast Cancer Study Group Trial 10-93. J Clin Oncol. 2006;24:337-344.

The incidence of breast cancer increases with age and breast cancer is the most common cancer in women older than 70 years old. 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. 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 data 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. This trial 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. Their 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 (QoL), disease-free survival (DFS), and overall survival (OS).

From May 1993 through December 2002, the study randomized 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. 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 proceed to axillary clearance. However, only 2 patients used this option. Radiotherapy using 2 tangential fields was recommended after breast-conserving surgery.

There were 473 patients who were equally balanced according to randomly assigned treatment arm. The median age was 74 years and 22% 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. 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. 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. This difference between treatments was no longer statistically significant at later follow-up assessments. 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. Overall, the 2 treatment groups were similar with respect to both DFS and overall survival. Within the ER-positive cohort the 2 treatment groups were similar with respect to both DFS and OS. Similarly, no treatment difference was observed for the ER-negative cohort for DFS and OS without axillary clearance. Sites of first event were similar between the 2 treatment groups. A 2% incidence of axillary recurrence overall (as first event) and no statistically significant difference between the 2 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.

Commentary

The morbidity of axillary dissection has led some investigators to question its necessity, whereas others have studied alternatives such as axillary radiation therapy and sentinel node biopsy. This randomized study examined the option of avoiding axillary surgery altogether and shows that in older women with clinically negative axillary examination, this transiently improves QoL apparently without compromising DFS or OS results. The median age of the patients enrolled into IBCSG Trial 10-93 was 74 years, which is substantially older than the median age in most adjuvant therapy trials conducted for postmenopausal patients. QoL measurements by both physician and patient showed significantly inferior arm-related QoL scores after axillary surgery. The authors concluded that axillary clearance does not contribute greatly to DFS or OS. 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).

Given the postoperative morbidity and the decrease in QoL associated with axillary surgery, especially for this elderly population, the trial results provide important evidence to support the option of avoiding axillary clearance. A recent randomized study conducted by the Cancer and Leukemia Group B (CALGB)1 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 2 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 the IBCSG 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 a potentially shorter life expectancy. Thus, the recent trend to substitute sentinel node biopsy can also be called into question, given that this present results seem to support avoidance of axillary dissection. This line of reasoning is based on the prior 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. Data for the 50- to 69-year age group from the Early Breast Cancer Trialists' Collaborative Group Overview demonstrate that for patients with endocrine-responsive disease, endocrine therapy (specifically tamoxifen) provides the majority of the advantage associated with adjuvant treatments.2 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 QoL. 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 QoL 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 a ongoing randomized clinical trials.

References

1. Hughes KS, et al. Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med. 2004;351:971-977.

2. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-1717.