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From The RACS SNAC Trial, C/- Breast, Endocrine & Surgical Oncology Unit, Royal Adelaide Hospital, Adelaide SA, Australia.
Correspondence: Address correspondence and reprint requests to: P. Grantley Gill, MD, The RACS SNAC Trial, C/- Breast, Endocrine & Surgical Oncology Unit, Level 6, East Wing Link, Royal Adelaide Hospital, North Terrace, Adelaide SA 5000, Australia; Fax: 61-8-8222-5896; E-mail: grantley.gill{at}adelaide.edu.au
ABSTRACT
The aim of the SNAC trial is to determine if sentinel node biopsy (SNB) produces less morbidity and equivalent cancer-related outcomes in comparison with immediate axillary clearance (AC) in women with early breast cancer. The intervention is SNB followed by immediate AC, or SNB followed by AC only if the SNB specimen is positive. This is a multicenter, centrally randomized phase III trial of 1000 women stratified according to age, tumor palpability, lymphatic mapping technique, and center. Accrual rate is 26 women per month; 789 women have been randomized to date. Analysis of the first 150 women indicates good compliance with study treatment and acceptable surgical technique.
Key Words: Axillary clearance • Breast cancer • Sentinel node
Axillary lymph node status is an important prognostic factor in early breast cancer and a key determinant of adjuvant therapy.1,2 Axillary clearance (AC) is the standard method in Australia for detecting nodal metastases. A proven method that accurately predicts axillary lymph node status and reduces the risk of lymphedema and other complications of AC would be a major advance.3,4 Sentinel node biopsy (SNB) can provide information regarding axillary lymph node involvement and may limit the morbidity associated with axillary surgery. Studies indicate that with optimal techniques SNB can predict the status of the remaining axillary lymph nodes in more than 95% of cases.5–8 The principal objective of the SNAC trial is to determine whether SNB (with AC only if the SNB specimen is positive) results in less morbidity than immediate AC and produces equivalent cancer-related outcomes for women with early breast cancer. The trial compares (1) axillary morbidity; (2) observer ratings and self-ratings of arm swelling, symptoms, and function; (3) axillary recurrence rates; (4) other aspects of quality of life; (5) overall survival and disease-free survival (local, distant, and both); (6) use of adjuvant therapies; and (7) number of surgical episodes and total number of days in hospital.
ELIGIBILITY AND STUDY DESIGN
All women with histologically or cytologically confirmed operable invasive breast cancer less than 3.0 cm in diameter who require axillary staging as part of their treatment are eligible for this trial. Major exclusion criteria include tumors greater than 3.0 cm in diameter, clinically involved axillary nodes, multicentric cancer, previously treated breast cancer, previous axillary surgery, failure to give informed consent, and ductal carcinoma in situ only. The study is a multicenter, centrally randomized, phase III clinical trial in two stages. Stage 1 (150 subjects) provides information about study procedures and outcome measures. Stage 2 (1000 subjects) provides the definitive comparison of the two treatments. Patients recruited in both stages are randomized, treated, and assessed in exactly the same way. All patients in stage 1 are also included in stage 2. After confirmation of eligibility, women are centrally randomized to SNB plus immediate AC (control arm) or to SNB alone (experimental arm) by the Clinical Trials Center of the National Health and Medical Research Council (NHMRC). Randomization is stratified to ensure balance for the following factors: age (less than 50 vs. greater than or equal to 50 years), primary tumor (palpable vs. not palpable), lymphatic mapping technique (blue dye plus lymphoscintigraphy vs. blue dye alone), and institution.
The study is performed in accordance with the NHMRC Statement on Ethical Conduct in Research Involving Humans (Commonwealth of Australia, 1999), the principles laid down by the 18th World Medical Assembly (Helsinki, 1964), and amendments laid down by the 29th (Tokyo, 1975), the 35th (Venice, 1983), the 41st (Hong Kong, 1989), and the 48th (Sommerset West, South Africa 1996) World Medical Assemblies. Participating hospitals must file a copy of the hospital ethics committee approval letter, and the approved patient information and consent sheets must first be filed with the NHMRC Clinical Trials Center. Written informed consent, in accordance with the NHMRC Statement on Ethical Conduct in Research Involving Humans, is obtained from all patients prior to randomization. It is understood that all data generated from this trial remain confidential and no report will contain any reference to patient names.
SURGERY AND PATIENT MANAGEMENT
Eligible women undergo normal preoperative assessment plus measurement of arm volume9 and detailed evaluation of arm sensation. All women complete questionnaires on global quality of life,10,11 body image after breast cancer,12 and self-rating of arm symptoms.
SNB is performed by the combined blue dye and scintigraphic techniques, unless nuclear medicine facilities are unavailable. On the day of surgery or the day before surgery, 20 to 40 mBq of technetium 99m-labeled antimony colloid in 2 to 4 mL of solution is injected around the tumor at four sites. Nuclear medicine staff members identify the sentinel node (SN) on the lymphoscintiscan and mark its location on the skin. In the operating room, 
2 to 4 mL of Patent Blue V dye is injected in four sites around the tumor immediately after induction of anesthesia. SNB is usually performed prior to tumor resection or mastectomy, and nodes that are hot (at least 10 times background activity) and/or blue are removed. Wide local excision or mastectomy is then performed in the usual manner. If no SNs are identified, then an axillary dissection is performed. Where nuclear medicine facilities are not available, localization of the SN is performed with blue dye alone. These cases are stratified separately.
Women randomized to immediate AC undergo standard dissection (level 1 and level II nodes) in conjunction with wide local excision or mastectomy. Women in the SNB arm undergo AC only if the SN is positive; the technique of AC is the same. If the SN is negative then no further axillary surgery is performed.
PATHOLOGICAL ASPECTS
In each case, the excised SNs are identified separately as SN 1, 2, or 3, according to decreasing levels of radioactivity detected at the time of surgery. They are also designated as hot and/or blue. Each entire node is grossly sliced into 2-mm slices, and four step sections are prepared at 200-micron intervals. If the node contains grossly visible metastatic disease, only one section is required. Sections are also prepared on coated slides and stained with the antikeratin antibody CAM 5.2 to detect smaller metastases. In patients undergoing AC, nonsentinel nodes are examined with one hematoxylin and eosin section.
FOLLOW-UP AND ASSESSMENTS
Women are assessed at 1, 6, and 12 months and then yearly for 5 years. Measurements of arm volume,9 sensation, and shoulder movement are taken and quality-of-life questionnaires are completed at each assessment. Data on survival and disease status are collected indefinitely. Standard adjuvant treatments are prescribed and administered according to the details of primary tumor pathology, axillary nodal status, and the type of surgical treatment (NHMRC guidelines).
STUDY OUTCOMES
The two treatments will be compared in terms of (1) early axillary morbidity; (2) observer ratings and self-ratings of arm swelling, symptoms, and function; (3) axillary recurrence rates; (4) other aspects of quality of life; (5) overall survival and disease-free survival (local, distant, and both); (6) use of adjuvant radiation therapy, chemotherapy, and endocrine therapy; (7) number of surgical episodes and total number of days in hospital; and (8) use of treatments for arm swelling, symptoms, and dysfunction. In addition, the SNAC trial will determine optimal measures of arm swelling, symptoms, and function and what constitutes clinically important differences in these measures.
Sample Size Calculations and Statistical Considerations
The numbers of axillary recurrences, relapses, and deaths will be small. The following estimates are based on observer ratings of arm swelling and on self-ratings of arm symptoms and function.
Arm Swelling
These calculations are based on subjective estimates of the proportions of women with significant arm swelling after AC and after SNB alone. A sample size of 1000 patients will yield greater than 80% power to detect a difference of 15% versus 9% with a two-sided P value of .05.
Self-Ratings of Arm Symptoms and Functions
A sample of 600 subjects (540 with complete data) will yield 90% power to detect a 10-point difference on a 100-point scale at the P = .01 level.
Because the numbers of axillary recurrences, relapses, and deaths will be small, a more realistic outcome is reduction in arm swelling. Based on observer estimates, a 15% incidence in arm swelling for women undergoing AC and a 6% reduction in arm swelling would be clinically worthwhile. A sample size of 1000 patients will yield greater than 80% power with 95% confidence to detect a difference in arm swelling from 15% in the AC arm to 9%. This sample size will also provide adequate power to detect a 10-point difference on the 100-point quality-of-life scales used in the study for patient-rated arm symptoms and functions.
The primary analysis for the study will be an intention-to-treat; secondary analyses will include only those patients found to have negative SNs (in both arms). Time-to-event analyses (e.g., time to recurrence, overall survival) will be summarized with Kaplan-Meier curves and compared with log-rank tests. Adjustments for prognostic factors will be made with use of Cox’s proportional hazards model or other suitable regression models. Because there will be few axillary recurrences and breast cancer deaths in this trial, definitive evidence about the effects of SNB on these outcomes will require a meta-analysis of all randomized trials.
INTERIM ANALYSES
An interim analysis is planned 3 months after randomization of 500 women, in addition to the stage 1 analysis of the first 150 women. The interim analysis will verify the safety and feasibility of study procedures and treatments by determining the proportions of patients in whom SNs are successfully identified and biopsied; the numbers of hematomas, aspirations for seromas, and grade 3 or greater infections; locoregional recurrence rates; and the proportions of women with significant arm swelling. This analysis will be blinded to any outcome results by treatment.
Interim analyses will be performed by the study statistician and reviewed by the independent safety and data monitoring committee (SDMC) and by the trial management committee. The SDMC consists of four people who are independent of the trial. The SDMC will make recommendations to the trial management committee about continuing, stopping, or modifying the trial on the basis of clear evidence from the interim analyses that (1) SNs are successfully identified and biopsied in fewer than 90% of subjects or (2) there is a significant difference between the treatments. These recommendations will be guided by notional significance levels of P < .003 (i.e., 3 standard deviations). No adjustment of the P values in the final analysis is required for these interim analyses.
ACCREDITATION
All participants submit a log of 20 consecutive operations, which is reviewed by the trial management committee (Table 1). Following approval of the log, a site visit to assess surgical technique and nuclear medicine facilities is conducted.
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The trial commenced in May 2001. Randomization continues currently at the rate of approximately 26 subjects per month (total, 789) at 26 participating centers in Australia and New Zealand (Table 2 and Fig. 1). Screening logs are kept in 10 of the centers to determine the rate of eligibility and recruitment. Between November 2001 and September 2002, 325 (54%) of 622 women were ineligible because of tumor size or axillary involvement. Of the 287 women (46%) who were eligible, 166 (58%) were randomized to the trial, 23 (8%) were not offered participation, and 98 (37%) declined participation.
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The SNAC trial is the first large multicenter study of surgical treatment of breast cancer in Australasia. The rapid recruitment of women and participating centers indicates that the target of 1000 subjects will be met rapidly and allow analysis of study outcomes in a timely manner. The preliminary analysis has established study compliance and acceptable standards of surgical technique. This trial does not have the power to detect differences in recurrence and survival, but the similarity in this design with other international studies such as ALMANAC and NSABP-B32 will allow its inclusion in a future meta-analysis of SNB. The SNAC trial will provide much new information on the quality of life of Australian women after breast cancer surgery, with particular reference to the relationship between subjective and objective changes in arm symptoms over time and perhaps on lymphedema. It will contribute much information about the morbidity of axillary surgery and its consequences.
ACKNOWLEDGMENTS
This study is supported by grants from the National Breast Cancer Foundation of Australia; the National Health & Medical Research Council of Australia; the Cancer Council of South Australia; and the Wesley Foundation.
The acknowledgments are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.
FOOTNOTES
The aim of the SNAC trial is to determine if sentinel node biopsy produces less morbidity and equivalent cancer-related outcomes in comparison with immediate axillary clearance in women with early breast cancer. Analysis of the first 150 women in the trial indicates good compliance with study treatment and acceptable surgical technique.
Received for publication November 14, 2003. Accepted for publication December 23, 2003.
REFERENCES
This article has been cited by other articles:
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  A. Luini, G. Gatti, B. Ballardini, S. Zurrida, V. Galimberti, P. Veronesi, A. R. Vento, S. Monti, G. Viale, G. Paganelli, et al. Development of axillary surgery in breast cancer Ann. Onc., February 1, 2005; 16(2): 259 - 262. [Abstract] [Full Text] [PDF]
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