Nsabp trial b

The B trial also validates that when the sentinel nodes are negative there is no significant difference in regional node recurrence between axillary node dissection and sentinel node resection. The results from Protocol B confirm previous reports 1 that patient-reported outcomes and morbidity related to range of motion, edema, pain, and sensory defects is lower in the sentinel node group compared with the axillary dissection group.

Randomized trials have been instrumental in effecting changes in the surgical management of breast cancer. The design of randomized trials for breast-conserving therapy and lymph node-sparing surgery are similar. The goals are to preserve tissue but still achieve the same cancer control. A reduction in morbidity is an obvious goal but the more challenging metric is demonstrating that survival is not adversely affected.

This narrow difference in survival was chosen to ensure that reduced morbidity would not occur at the expense of reduced survival. This required high total accrual and is why the B trial is the largest randomized surgical trial in breast cancer yet performed. One measure of quality in trial design is the clarity of the goals.

Disclosure of trial results was allowed only when overall survival endpoints were met. Assessing narrow differences in the primary outcomes in such a large group of patients mandated careful control of the trial conditions.

Patient factors in this trial were well controlled and balanced. This was further validated by the survival results which, when evaluated with all of the stratification variables combined, yielded no significant differences. Potential imprecision was possible because of the complexity of surgical and pathological procedures. Variation was controlled by a careful preregistration training program that focused on protocol compliance.

Of the surgeons audited, the outcomes were excellent. Other sentinel node trials include the American College of Surgeons Oncology Group trial Z that randomized patients with pathologically positive sentinel nodes to axillary dissection or sentinel node only. A trial from Milan has reported data with follow up to 10 years.

Data combined from available randomized trials of axillary dissection versus no axillary surgery indicated a modest survival advantage to axillary dissection. It is a highly targeted removal of the lymph nodes receiving direct drainage from a solid tumor in the breast. The results from B demonstrate that in the sentinel node-negative population, any survival advantage to full axillary dissection is fully mitigated by simply removing the sentinel nodes.

Surgeons should continue to strive to optimize the methods of sentinel node surgery. For example, removal of only a single sentinel node increases the risk for false-negative sentinel node resection. Improving methods to validate that the nodes removed are in fact on the immediate drainage pathway from the cancer is important. In summary, in NSABP Protocol B, overall survival, disease-free survival, and regional control between the treatment groups were statistically equivalent.

We conclude that when the sentinel node is negative, sentinel node surgery alone with no further axillary dissection is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes. No randomized trial results addressing survival or regional control were published at the time that NSABP Protocol B began accruing patients.

At present, there are references to twenty different sentinel node studies in breast cancer patients in which there was a randomization component. None of these twenty trials report survival data explicitly comparing sentinel node versus axillary dissection in sentinel node-negative patients. All sentinel node studies with a randomization component that have reported on more than patients are described in the report presented here.

NSABP Protocol B adds to the totality of evidence in breast cancer patients by definitively demonstrating that there is no significant difference in survival between axillary dissection and sentinel node surgery alone in patients with negative sentinel nodes. It also adds information to existing reports related to regional control and morbidity.

Role of the funding source: The authors are responsible for all decisions related to the study design, analysis and interpretation of the data, writing of this report, and the decision to submit for publication.

The authors wish to thank Barbara C. Good, PhD, and Wendy L. Rea for editorial assistance, and Elaina Harper for data management. Role of the funding source: The role of the funding source NCI is to support the clinical trials groups and their members.

Potential conflicts of interest: Dr. Harlow reports receiving a grant to his institution from the NCI. Professor Costantino reports receiving a grant to his institution from the NCI. Professor Ashikaga reports receiving a grant to his institution from the NCI. Weaver reports grants and grants pending to his institution from the NCI.

Scarth reports grants to his institution via the NSABP for patient accrual and administrative support. All of the authors had access to the raw data.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.

As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form.

Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. National Center for Biotechnology Information , U. Lancet Oncol. Author manuscript; available in PMC Aug 1. David N. Krag , MD, 1, 2 Stewart J. Anderson , PhD, 1, 3 Thomas B. Julian , MD, 1, 4 Ann M. Brown , ScD, 1, 3 Seth P. Harlow , MD, 1, 2 Joseph P. Costantino , Dr.

PH, 1, 3 Takamaru Ashikaga , Ph. Weaver , MD, 1, 2 Eleftherios P. Mamounas , MD, 1, 5 Lynne M. Jalovec , M. Frazier , M. Dirk Noyes , M. Stewart J. Thomas B. Ann M. Seth P. Joseph P. Donald L.

Eleftherios P. Lynne M. Thomas G. Dirk Noyes. Hugh M. Author information Copyright and License information Disclaimer. Correspondence and reprints to: David Krag, M. I confirm that I had full access to all the data in this study and I am responsible for the decision to submit this work for publication. Contributors: Dr. Krag — Principle investigator. Professor Anderson — Data preparation; data analysis; manuscript writing and review. Julian — Protocol management; institutional principle investigator; writing of manuscript.

Brown — Dataform development; article review and critique. Harlow — Co-investigator in charge of surgical training for trial. Professor Costantino — Data collection; interpretation of results; manuscript review; editing; final approval. Professor Ashikaga — Manuscript review.

Mamounas , MD. Author information Article notes Copyright and License information Disclaimer. Received Jan 28; Accepted Sep This article has been cited by other articles in PMC. Abstract Over the past 40 years, the National Surgical Adjuvant Breast and Bowel Project NSABP has conducted several large, randomized clinical trials evaluating various aspects of surgical and adjuvant therapy in patients with operable breast cancer.

Open in a separate window. Figure 1. Trial evaluating sentinel node biopsy in patients with invasive, operable breast cancer NSABP B trial Despite several decades of clinical investigations focusing on the prognostic factors for recurrence in patients with operable breast cancer, the status of the axillary lymph nodes has remained the single most important independent factor predicting outcome.

Figure 2. Pivotal NSABP trials in patients with ductal carcinoma in situ As randomized trials demonstrated the value of breast conserving surgery in patients with invasive breast cancer, an obvious question arose relative to the value of this procedure in patients with non-invasive disease.

Figure 3. Figure 4. Figure 5. Studies in patients with ER-negative tumors The first trial NSABP B randomized patients with negative nodes and negative estrogen receptors to surgery alone, or surgery followed by 12 months of adjuvant chemotherapy with methotrexate and sequentially administered 5-FU [methotrexate and fluorouracil MF ] followed by leucovorin figure 6.

Figure 6. Figure 7. Studies in patients with ER-positive tumors In parallel to the studies evaluating chemotherapy and tamoxifen in patients with node-negative, ER-negative breast cancer, the NSABP launched a series of trials evaluating tamoxifen and the combination of tamoxifen plus chemotherapy in patients with node-negative, ER-positive disease.

Figure 8. Figure 9. Figure Studies evaluating taxanes as adjuvant therapy Given the disappointing results from the studies of dose intensification in patients with node-positive breast cancer, the introduction of new agents with novel mechanisms of action became an important alternative approach to increase treatment effectiveness. Studies evaluating biologically targeted therapies in the adjuvant setting Despite considerable progress with adjuvant chemotherapy, there are still significant limitations with this approach both in terms of efficacy and, more importantly, in terms of toxicity.

Studies evaluating bisphosphonates as adjuvant therapy Bisphosphonates are emerging as a class of drugs with great potential for improving the outcome of breast cancer without adversely affecting patients' quality of life and without causing significant toxicity.

SUMMARY This review summarizes the results from several pivotal NSABP breast cancer clinical trials that in a step-wise fashion, evaluated various loco-regional and systemic therapy approaches in the management of patients with operable breast cancer. References 1. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation.

N Engl J Med. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast.

Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer.

National Surgical Adjuvant Breast and Bowel Project: Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. Sentinel lymphadenectomy in breast cancer.

Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol. The sentinel node in breast cancer-a multicenter validation study. Sentinel lymph node biopsy for breast cancer: a suitable alternative to routine axillary dissection in multi-institutional practice when optimal technique is used.

Multicenter trial of sentinel node biopsy for breast cancer using both technetium sulfur colloid and isosulfan blue dye. Ann Surg. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymphnodes. Prevention of invasive breast cancer in women with ductal carcinoma in situ : an update of the national surgical adjuvant breast and bowel project experience.

Semin Oncol. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B Tamoxifen for early breast cancer: an overview of the randomised trials.

A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors.

J Natl Cancer Inst. Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Br J Cancer. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial. Contralateral primary tumors in breast cancer patients in a randomized trial of adjuvant tamoxifen therapy. Cyclophosphamide and tamoxifen as adjuvant therapies in the management of breast cancer. Jordan VC. Eur J Cancer.

Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B randomised controlled trial.

Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. Arimidex Study Group. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.

Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial.

ATAC Trialists' Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. J Natl Cancer Inst Monogr. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogenreceptor-negative tumors.

Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project NSABP B and first report of findings from NSABP B comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil.

Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer. Analysis at six years by Nolvadex Adjuvant Trial Organisation. Improved survival among patients treated with adjuvant tamoxifen after mastectomy for early breast cancer. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B randomized trial.

Phase I and endocrine study of exemestane FCE , a new aromatase inhibitor, in postmenopausal women. Cancer Res. Lemmens J, et al. Exemestane experience in breast cancer treatment. J Steroid Biochem Mol Biol.

Endocrinological and clinical evaluation of exemestane, a new steroidal aromatase inhibitor. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. S-phase fraction combined with other patient and tumor characteristics for the prognosis of node-negative, estrogen-receptor-positive breast cancer.

Breast Cancer Res Treat. Skipper HE. Kinetics of mammary tumor cell growth and implications for therapy.

A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep. Effect of surgical removal on the growth and kinetics of residual tumor. Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.

Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B Fisher B, Mamounas EP. Preoperative chemotherapy: a model for studying the biology and therapy of primary breast cancer.

Mamounas EP. Preoperative doxorubicin plus cyclophosphamide followed by preoperative or postoperative docetaxel. Oncology Huntingt ; 11 — Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B The efficacy of recombinant human granulocyte colonystimulating factor and recombinant human granulocyte macrophage colony-stimulating factor in permitting the administration of higher doses of cyclophosphamide in a doxorubicin-cyclophosphamide combination.

Am J Clin Oncol. Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B Mamounas E. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study.

Combined doxorubicin and paclitaxel in advanced breast cancer: effective and cardiotoxic. Ann Oncol. Dieras V. Docetaxel in combination with doxorubicin: a phase I dose-finding study. Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

Phase II trial of doxorubicin and docetaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: Eastern Cooperative Oncology Group Study E Paterson AH. The potential role of bisphosphonates as adjuvant therapy in the prevention of bone metastases.

A high incidence of vertebral fracture in women with breast cancer. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer.

Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. Support Center Support Center. Fisher B, et al. The New England Journal of Medicine. Categories : Reviewable articles Surgery Oncology. Navigation menu Personal tools Create account Log in. Namespaces Page Discussion. Views Read View source View history. This page was last modified on 31 December , at