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From the Departments of Surgery (DNK, SPH), Pathology (DLW), and Medical Statistics (TA, RMS), University of Vermont, Burlington, Vermont; National Surgical Breast and Bowel Project (TBJ, NW); and the University of Pittsburgh (JB), Pittsburgh, Pennsylvania.
Correspondence: Address correspondence and reprint requests to: David N. Krag, MD, College of Medicine, University of Vermont, Given Building E309, Burlington, VT 05405; Fax: 802-656-5833; E-mail: David.Krag{at}uvm.edu
ABSTRACT
The NSABP-32 trial is a randomized, phase III clinical trial to compare sentinel node (SN) resection to conventional axillary dissection in clinically node-negative breast cancer patients. The primary aims of the trial are to determine if removal of only SNs provides survival and regional control equivalent to those of axillary dissection, while diminishing the magnitude of surgically related side effects. In order to ensure consistency of the outcomes for this trial, a standardized method of SN surgery has been utilized for all cases. A secondary aim of the B32 trial is to evaluate whether patients with "occult" metastases in the SNs have worse survival. Accrual is taking place at 73 institutions in North America, and 217 surgeons are enrolling patients.
Key Words: Breast cancer • Clinical trial • Sentinel node • Survival
The NSABP-32 trial is a randomized, phase III clinical trial to compare sentinel node (SN) resection to conventional axillary dissection in clinically node-negative breast cancer patients. Patients are stratified by age, clinical tumor size, and type of surgery. Group 1 undergoes an SN resection and an axillary resection in all cases. Patients in group II have the SNs removed that are evaluated intraoperatively and postoperatively for the presence of cancer cells. If the SNs are negative for cancer, no further axillary surgery is performed.
The primary aims of the trial are to determine if removal of only SNs provides survival and regional control equivalent to those of axillary dissection, while diminishing the magnitude of surgically related side effects. The trial is designed to detect just under a 2% survival difference between the two treatment groups.
Axillary dissection has been part of conventional surgical management of breast cancer for more than a century. The rationale for performing this surgery is to maximize the number of patients cured of breast cancer, to provide long-term regional control, and to provide prognostic information. This prognostic information provides an estimate for patients of their chances of being cured. In only a minority of cases will this information alter recommendations for systemic adjuvant therapy.
Unlike that available for SN surgery, extensive information is available on the long-term outcomes of axillary dissection. Six prospective, randomized clinical trials have been performed comparing axillary dissection to a control group in which no initial axillary resection was performed.1–6 The key finding that emerged from these trials is that in every single study, the observed survival was higher in the group that was randomized to initial axillary resection. The overall magnitude of the improved survival due performance of axillary resection was about 5%.7 Arguments that this amount of survival difference is insignificant8 are not consistent with modern concepts of breast cancer treatment. For example, conventional polychemotherapy for postmenopausal women results in survival improvement of about 2% to 3% yet is integral to standard treatment recommendations.9 Bland et al.10 analyzed a large database of more than 500,000 women treated for breast cancer and noted that there was a trend in the United States to omit axillary dissection. They noted that in this database there was an observed 10-year survival among patients with axillary surgery of 85%, but it was only 66% among patients for whom this treatment was omitted. This led to their conclusion that "lymphadenectomy is therapeutic and diagnostic."
The justification for conducting a clinical trial in which a treatment (axillary dissection) that improves survival by 5% is omitted is based on the remarkable accuracy of SN technology. Inherent in the equivalency hypothesis of the NASBP-32 trial is that SN surgery will identify those patients for whom axillary surgery is and is not necessary. These are not trivial assumptions, because failure of SN surgery to provide equal therapeutic value as axillary node resection may lead to increased death rates. Because the ultimate goal of SN surgery is to lessen morbidity, an increase in the death rate to achieve that goal would be unreasonable.
It is attractive to make the logical conclusion that if the sentinel lymph nodes are determined to be negative by pathological examination, there is no need to perform additional surgery. If all nodes are negative, there can be no possible benefit to the patients. However, this assumes that the microscopic inspection of the lymph nodes is essentially thorough and perfect and a pathologically negative node truly contains no cancer cells. Several years ago an analysis was made on the impact that removal of different numbers of lymph nodes had on survival when all the lymph nodes were determined pathologically to be negative. When analyzed by 1 to 5 nodes, 6 to 10, 11 to 15, 16 to 20, and 20 to 25 negative nodes removed, the respective observed survival rates were 74%, 76%, 77%, 79%, and 81%.11 More recent data obtained from the SEER database, which included more than 70,000 women with breast cancer, identified a similar trend of improved survival with removal of greater numbers of pathologically negative nodes.
In summary, in six prospective randomized trials comparing axillary dissection with no initial axillary dissection, the observed survival was reported higher in the axillary dissection group. Nonrandomized data for large groups of women with breast cancer demonstrate that the group that underwent axillary dissection had a higher survival rate. In addition, analysis of a large modern database of women with breast cancer shows higher survival among women who had a higher number of lymph nodes removed, even when the lymph nodes were determined to be pathologically negative. Any alternative to axillary resection, including SN surgery, warrants definitive comparison of survival outcomes.
The second primary aim of the B32 clinical trial is to determine if SN-only resection provides equivalent control of regional disease. As with survival, extensive information is available regarding outcomes with axillary resection, but the long-term data on SN surgery are few. Axillary dissection provides close to 100% long-term regional control in the axillary node region. Observation alone without initial axillary dissection leads to clinical recurrences at the rate of approximately 20% in the axilla as the first site of recurrence. A challenge with utilizing axillary recurrence as an endpoint in any trial is that determination of the presence of cancer in lymph nodes by clinical examination is rather inaccurate. A further difficulty is that clinically detected axillary recurrences in patients who have not had axillary node resection can continue to occur over several years.12 Therefore, conclusions can potentially be biased by the inaccuracy of clinical examination and by insufficient periods of observation.
The third primary aim of the B32 trial is to compare the magnitude of morbidity and quality-of-life differences between the two treatment arms. Functional (sensory, range of motion, and pain) parameters are assessed. Edema is quantitated by volume of displaced water. Measurements are made by immersion in a calibrated cylinder. Both study groups are measured preoperatively and intermittently throughout the duration of the observation period.
There is wide variation in the methods of SN surgery. In order to insure consistency of the outcomes for this trial, a standardized method has been utilized for all cases. Technetium sulfur colloid is injected around the primary tumor 30 minutes to 8 hours before surgery. A second small dose of technetium sulfur colloid is injected into the skin over the tumor. Blue dye is injected around the primary tumor about 5 minutes prior to surgical exploration for the SNs. A lymph node is considered an SN if it is radioactive and/or blue or is rock-hard and clinically positive. Extra-axillary nodes that meet the definition of being sentinel are removed.
Core trainers made site visits to each participating hospital. At that visit a team review was made with the surgeon, nuclear medicine group, operating room nursing personnel, and data management personnel. In addition, the core trainers participated in surgery and confirmed that the methods for SN surgery were performed according to the trial plan. Surgeons who had little prior experience completed a minimum of five cases in which the procedure was successfully completed according to the methods in this trial. Surgeons who provided documentation of prior experience with a minimum of 10 cases needed to complete only one successful "training" case. Determinants for success include adherence to the methods, generation of appropriate source documentation, and completion of data forms. Surgeons who completed the training process and were approved for handling randomized cases could then serve as the intraoperative mentors to other surgeons at that same site.
All participating surgeons have their first 20 randomized cases evaluated for consistency of methods and for overall quality control of data entry. Approval to continue entry of cases is contingent upon successful review of the randomized cases.
A secondary aim of the B32 trial is to evaluate "occult" metastases in the SNs. Initial processing of SNs is by sectioning nodes at 2-mm to 3-mm intervals and staining the slides with hematoxylin and eosin (H&E). Sentinel nodes in which cancer is not identified by this method are sent to a core pathology laboratory at the University of Vermont, where additional evaluation is performed, with blinding of the clinical status of the patient. Additional sections are made and stained with an anticytokeratin cocktail. Preliminary data indicate that between 10% and 20% of cases that are node-negative by H&E will be positive by immunohistochemistry (IHC). The B32 trial will determine whether the survival of patients who have occult tumor cells is worse than that of patients negative by both H&E and IHC.
The B32 trial opened in 1999. Accrual is taking place at 73 institutions in North America, and 217 surgeons are enrolling patients. The surgeons and participating physicians in this clinical trial have demonstrated a significant commitment to obtaining accurate and meaningful information for their current and future patients.
ACKNOWLEDGMENTS
This research was supported by the Vermont Cancer Center/National Cancer Institute (grant U01 CA74137) and by PHS grants U10-CA12027, U10-CA69651, U10-CA37377, and U10-CA69974 awarded by the National Cancer Institute and DHHS.
The acknowledgments are are available online in the fulltext version at www.annalssurgicaloncology.org. They are not available in the PDF version.
FOOTNOTES
The primary aims of the NSABP-32 trial are to determine if removal of only sentinel nodes provides survival and regional control equivalent to that of axillary dissection, while diminishing the magnitude of surgically related side effects.
Received for publication September 22, 2003. Accepted for publication December 11, 2003.
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