Treatment of Early-Stage Breast Cancer National Institutes of Health Consensus Development Conference Statement June 18-21, 1990 This statement is more than five years old and is provided solely for historical purposes. Due to the cumulative nature of medical research, new knowledge has inevitably accumulated in this subject area in the time since the statement was initially prepared. Thus some of the material is likely to be out of date, and at worst simply wrong. For reliable, current information on this and other health topics, we recommend consulting the National Institutes of Health's MedlinePlus http://www.nlm.nih.gov/medlineplus/. This statement was originally published as: Treatment of Early-Stage Breast Cancer. NIH Consens Statement 1990 Jun 18-21;8(6)1-19. For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used: Treatment of Early-Stage Breast Cancer. NIH Consens Statement Online 1990 Jun 18-21 [cited year month day];8(6)1-19. Abstract The National Institutes of Health Consensus Development Conference on Treatment of Early-Stage Breast Cancer brought together surgical, radiation, and medical oncologists, biostatisticians, psychologists, nurses, and other health care professionals as well as the public to address: the roles of mastectomy versus breast conservation, the role of adjuvant therapy, and the use of prognostic indicators in the treatment and management of early-stage breast cancer. Following 2 days of presentations by experts and discussion by the audience, a consensus panel weighed the evidence and prepared their consensus statement. Among their findings, the panel recommended that (1) breast conservation treatment is an appropriate method of primary therapy for the majority of women with Stage I and II breast cancer and is preferable because it provides survival equivalent to total mastectomy and axillary dissection while preserving the breast; (2) the majority of patients with node negative breast cancer are cured by surgery or by surgery and radiation without further therapy; (3) there is clear evidence that the rate of local and distant recurrence is decreased by both adjuvant combination cytotoxic chemotherapy and by adjuvant tamoxifen; (4) the decision to use adjuvant treatment should follow a thorough discussion with the patient regarding the possible risks and toxicities of therapy and its impact on quality of life; and (5) patients with tumors less than or equal to 1 centimeter have an excellent prognosis and do not require adjuvant therapy outside the clinical trials. The full text of the consensus panel's statement follows. Introduction Carcinoma of the breast is the most common malignancy in women in the United States. As a cause of cancer death in women, breast cancer is exceeded only by lung cancer. The incidence of breast cancer has been rising steadily over the past decade. In the 1990's, more than 1.5 million women will be newly diagnosed with this disease; nearly 30 percent of these women will ultimately die from breast cancer. The increased number of reported cases may be partially attributable to their detection following more widespread use of screening mammography. Most of the increase has been in patients with smaller primary breast tumors. In 1982, approximately 12,000 women were diagnosed with tumors less than 2 centimeters in diameter and negative axillary lymph nodes. That number had risen to 32,000 by 1986. For those patients with axillary node positive breast cancer, there has been a less dramatic increase in tumors less than 2 centimeters (3,000 in 1982 to 7,000 in 1986) while there has been a decrease in the number presenting with tumors larger than 5 centimeters. Of the 150,000 new patients diagnosed with invasive breast cancer in 1990, 75 to 80 percent will have clinical Stage I or II disease, and approximately two-thirds of these will have no involvement of the axillary lymph nodes. Traditional concepts through most of the 20th century held that breast cancer was a local/regional disease best managed by radical mastectomy. Over the past 20 years, there have been several clinical trials worldwide that have compared less extensive breast resections with standard radical mastectomy. These have included comparisons of total mastectomy (with and without radiation therapy and axillary lymph node dissection) with radical mastectomy. Subsequent studies have compared different approaches to breast conservation surgery with total mastectomy. At present, breast conservation therapy is used in a minority of patients. The appropriate use of breast conservation involves a variety of clinical, biological, and psychosocial factors that merit public debate. Adjuvant therapy has become the standard of care for the majority of breast cancer patients with axillary lymph node involvement. More recently, several randomized trials from North America and Europe have shown an improvement in disease-free survival for node negative breast cancer patients receiving adjuvant therapy. Absence of metastasis to the axillary lymph nodes has traditionally been considered a favorable biologic condition for patients with invasive breast cancer. However, all patients with node negative breast cancer are at risk for disease recurrence. Intensive efforts to define an individual patient's risk of recurrence have produced a plethora of potential prognostic factors, from patient characteristics to histologic, biochemical, and molecular characteristics of the tumor. The importance of these various prognostic factors has been the subject of controversy. To evaluate the developing results of breast conservation, adjuvant therapy of node negative breast cancer, and clinical prognostic factors, the National Cancer Institute and the Office of Medical Applications of Research of the National Institutes of Health convened a Consensus Development Conference on the Treatment of Early-Stage Breast Cancer on June 18-21, 1990. After 2 days of presentations by experts and discussion by the audience, a consensus panel drawn from specialists and generalists from the medical profession and related scientific disciplines, clinical investigators, methodologists, and public representatives considered the evidence and agreed on answers to the following key questions: What are the roles of mastectomy versus breast conservation in the treatment of early stage breast cancer? What are the optimal techniques for breast conservation? What is the role of adjuvant therapy for patients with node negative breast cancer? How should prognostic factors be used in the management of node negative breast cancer? What are the directions for future research? What Are the Roles of Mastectomy Versus Breast Conservation in the Treatment of Early-Stage Breast Cancer? Breast conservation treatment is an appropriate method of primary therapy for the majority of women with Stage I and II breast cancer and is preferable because it provides survival equivalent to total mastectomy and axillary dissection while preserving the breast. In general, primary therapy for Stage I and II breast cancer consists of breast conservation treatment or total mastectomy. Breast conservation treatment is defined as excision of the primary tumor and adjacent breast tissue*, followed by radiation therapy. Total mastectomy is an appropriate primary therapy when breast conservation treatment is not indicated or selected. Both surgical therapies are accompanied by axillary dissection, which provides important prognostic information. * This procedure is also referred to as lumpectomy, segmental mastectomy, or partial mastectomy. Prospective randomized trials comparing breast conservation treatment with total mastectomy with maximum followup of 17 years have demonstrated equivalent results as measured by overall patient survival. Important considerations in the choice of therapy for women with Stage I and II breast cancer include clinical criteria, factors that influence local/regional tumor control, cosmetic results, psychosocial issues, and patient preferences for treatment method. Patient Selection In the selection of women for breast conservation treatment or mastectomy, certain women are not candidates for breast conservation treatment: Women with multicentric breast malignancies, including those with gross multifocal disease or diffuse microcalcifications detected by mammography. Patients for whom breast conservation treatment would produce an unacceptable cosmetic result. Examples include women whose tumors are large relative to breast size and those with certain collagen vascular diseases. Certain pathologic and clinical factors may influence treatment selection because of their potentially adverse impact on local recurrence after breast conservation treatment. Controversy exists about these factors, examples of which include the presence of extensive intraductal carcinoma within and adjacent to the primary tumor, extensive lymphatic involvement, and young age (under 35-39 years). Prospective studies comparing primary therapies have included women whose primary tumors were usually less than or equal to 4 centimeters in diameter. Local Control Local control is a major goal of breast conservation treatment. The incidence of local recurrence is low in appropriately selected patients receiving optimal breast conservation treatment. Results of randomized trials have suggested that the use of adjuvant chemotherapy or hormonal therapy further reduces the rate of local recurrence after breast conservation treatment. Cosmetic Result A goal of primary breast cancer treatment is to produce the best cosmetic result consistent with achievement of local/regional control. In clinical trials, the majority of patients achieve good to excellent cosmetic results after breast conservation treatment. Optimal long-term results require integration of careful surgical excision and precise radiotherapy techniques. When mastectomy is indicated or selected, breast reconstruction should be considered to improve the cosmetic result. Psychosocial Factors Women should be educated about treatment choices and clinical trial options in order to make an informed decision in consultation with their physicians. A variety of factors have a major influence on a woman's choice of primary therapy. These include logistic and emotional considerations, personal financial issues, and proximity and access to appropriate medical care. A woman's body image and her beliefs and concerns may determine her preference for breast conservation treatment or mastectomy.   What Are the Optimal Techniques for Breast Conservation? The objective of breast conservation is to obtain a high probability of local control, with survival at least equivalent to that obtained with total mastectomy and axillary dissection, combined with maximal cosmetic results and maintenance of normal function. The most widely used treatment that achieves these goals is the combination of local surgical excision, axillary dissection, and postoperative radiation therapy. Although this treatment approach produces survival equivalent to mastectomy, with a high likelihood of good cosmesis and function, further studies are required to refine certain treatment details. The following recommendations define the treatment details deemed optimal based on the available data. Surgical Recommendations The diagnosis should be established by fine needle aspiration cytology, limited incisional biopsy (particularly for larger lesions), or definitive wide local excision. The type and placement of incisions can influence greatly the quality of cosmesis. Arcuate incisions with thick flaps, centered over the lesion, are superior to radial incisions, particularly for upper quadrant lesions. Routine excision of overlying skin is unnecessary except for very superficial lesions. Careful hemostasis is essential and drains are rarely necessary. In most instances, suture reapproximation of mammary tissue should be avoided. It is appropriate to excise the primary lesion with a normal tissue margin of approximately 1 centimeter. The intent of this recommendation is to achieve a surgical margin that is grossly and microscopically uninvolved with tumor. To obtain adequate pathological evaluation, it is necessary to mark the specimen for proper orientation and to ink the resection margins. When margins are grossly involved with tumor, further resection is indicated. Available data are inadequate to determine whether focal microscopic involvement of a margin increases the risk of local failure after optimal radiation therapy. Because cosmetic result is related to the amount of tissue excised, unnecessarily wide margins (> 2 cm) should be avoided. Because nodal status is the most important available prognostic factor, a Level I-II axillary dissection should be routine both for staging and for prevention of axillary recurrence. Separate incisions should usually be employed for the primary tumor excision and the axillary dissection to enhance functional and cosmetic results. Radiation Therapy Recommendations Megavoltage radiation therapy to the whole breast to a dose of 4,500 to 5,000 cGy (180 to 200 cGy per fraction) should be routinely used. Boost irradiation has been used in the majority of trials to date. However, the precise indications are not well defined. In the reported trials, the patients with focal microscopic involvement of margins have been treated with boost irradiation or mastectomy. There are no current data to support lesser treatment for these patients. Treatment planning should be done to minimize radiation exposure to lung and heart and to achieve uniform dosage to the treatment volume. Boost irradiation should be delivered by electron beam or implantation to doses of 1,000 to 1,500 cGy. Higher doses produce a greater incidence of cosmetic impairment. If a Level I-II axillary dissection has been performed, axillary nodal irradiation is not routinely indicated. No data indicate any increased risk of secondary malignancies or contralateral breast cancers resulting from breast irradiation. Longer followup of this population is necessary to resolve this issue fully. Although local control can be obtained in some patients with local excision alone, no subgroups have been identified in which radiation therapy can be avoided. In patients receiving adjuvant chemotherapy, no precise recommendations regarding the sequence and timing of radiation therapy and chemotherapy can be made. A small percentage of patients will develop a local recurrence following breast conservation therapy. Total mastectomy is effective salvage therapy for a substantial percentage of these patients. This is in contrast to the poor prognosis associated with local chest wall recurrence following mastectomy. Hence, in patients treated with breast conservation, long-term careful breast monitoring with physical examination and mammography is essential for early detection and treatment of local recurrence. What Is the Role of Adjuvant Therapy for Patients With Node Negative Breast Cancer? The majority of patients with node negative breast cancer are cured by breast-conserving treatment or total mastectomy and axillary dissection. There is clear evidence that the rate of local and distant recurrence is decreased by both adjuvant combination cytotoxic chemotherapy and by adjuvant tamoxifen. Data from the 10 randomized trials reviewed show that adjuvant systemic therapy reduces the rate of recurrence by approximately one-third, with a broad range. For example, among a group of women with a 30 percent risk of recurrence adjuvant therapy would decrease that risk to about 20 percent. The role of these treatments in improving overall survival and other important parameters such as quality of life is still being defined. The completed studies are not large enough, nor is the followup long enough, to estimate with acceptable precision the interactions between menopausal status or steroid receptor positivity and the effects of adjuvant therapy in node negative patients. Although all patient subsets experience lower rates of recurrence, relatively few patients with estrogen receptor-negative tumors have been included in tamoxifen studies. At the present time, reduced mortality is seen in nearly all trials but is not statistically significant in most. However, the rate of death in node negative patients is low, so a clinically important reduction in mortality may require a long followup to achieve statistical significance. For chemotherapy, more benefit is seen in trials in which antimetabolites (methotrexate and 5-fluorouracil) are administered intravenously than in trials in which they are given orally. For tamoxifen, studies using the drug for more than 2 years (usually 5 years) seem to result in greater reductions in the rate of recurrence than studies using shorter courses. In prospective studies in node negative patients, tamoxifen reduces the clinical incidence of contralateral primary breast cancer. The overall benefits from tamoxifen in postmenopausal patients clearly outweigh any toxicities currently described. In premenopausal patients, the administration of tamoxifen may cause endocrine abnormalities with uncertain long-term consequences. Although there does not appear to be an excess number of cases of endometrial carcinoma in tamoxifen-treated premenopausal patients, the followup durations are too short to predict confidently whether or not this will occur. The influence of tamoxifen on the developing fetus is unknown. There are no data now available concerning the effects of combination chemotherapy plus tamoxifen in node negative patients. Trials addressing this issue are under way. Recommendations The many unanswered questions in the adjuvant systemic treatment of node negative breast cancer make it imperative that all patients who are candidates for clinical trials be offered the opportunity to participate. The following recommendations apply only to patients who are not candidates for such trials or who refuse participation. All node negative patients should be made aware of the benefits and risks of adjuvant systemic therapy. The decision to use adjuvant treatment should follow a thorough discussion with the patient regarding the likely risk of recurrence without adjuvant therapy, the expected reduction in risk with adjuvant therapy, toxicities of therapy and its impact on quality of life. Some degrees of improvement may be so small that they are outweighed by the disadvantages of therapy. Adjuvant therapy should consist of either combination chemotherapy or tamoxifen (20 mg/day for at least 2 years). No completed studies have directly compared tamoxifen with chemotherapy (with or without tamoxifen) in node negative patients. Tamoxifen has less acute toxicity than chemotherapy, but no statement is possible regarding chronic toxicity or comparative efficacy. The results of current and future trials concerning the safety of tamoxifen in premenopausal patients must be followed carefully.    How Should Prognostic Factors Be Used in the Management of Node Negative Breast Cancer? Prognostic factors should be used to provide an estimate of risk of recurrence in women with early-stage breast cancer. Although no individual patient can be assured that she has no risk of recurrence, the majority of women will be cured with local/regional therapy. A useful prognostic factor has the following characteristics: It has significant and independent predictive value that has been validated by clinical testing. Its determination must be feasible, reproducible, and widely available, with quality control. It must be readily interpretable by the clinician and have therapeutic implications Prognostic Factors Tumor Size. There is a strong correlation between tumor size and risk of recurrence. Even within the T1 category, there is variation in risk. Tumors less than or equal to 1 centimeter have a particularly good prognosis (e.g., < 10 percent recurrence at 10 years) relative to tumors 1.1 to 2 centimeters in diameter. In general, the risk of recurrence increases with increasing tumor size. The pathologist should perform a careful gross examination with documentation of tumor size. Estrogen and Progesterone Receptor Status. Patients with receptor-positive tumors have a better prognosis than those with receptor-negative tumors. However, the difference in recurrence rates at 5 years is only 8 to 10 percent. Nuclear Grade. This is a well-documented factor. When determined by experienced pathologists, it discriminates favorable and unfavorable prognostic groups. High nuclear grade is associated with a higher rate of recurrence. Nuclear grade is not currently part of the routine pathologic review of breast cancer specimens. The pathology community should adopt a uniform grading system and routinely use this discriminant. Histologic Type. Several well-characterized histologic subtypes impart a favorable prognosis, although they are a distinct minority of all breast cancer cases. These subtypes include tubular, colloid (mucinous), and papillary types. Proliferative Rate. Measurements of cellular proliferation in breast cancer specimens using a variety of techniques have shown a strong correlation with outcome. DNA flow cytometry has become widely available for the determination of S-phase fraction as well as ploidy status. S-phase fraction does correlate with prognosis, but ploidy status alone is not of clear prognostic value. Up to 25 percent of specimens are not evaluable by flow cytometry because of methodologic problems. Because of the complexity of the technology, quality control is especially critical. Although S-phase fraction has been shown to be an independent prognostic factor in some studies, its clinical value is being defined. Other Factors. High levels of the protease cathepsin D are associated with an unfavorable prognosis. Data for HER-2/neu, epidermal growth factor receptor, and stress-response (heat shock) proteins are of interest, but further investigation is required before reaching any conclusions about their clinical value. Estimating Individual Risk Currently available prognostic factors are associated with a broad range of risk of recurrence in node negative breast cancer patients. There are extremes of high and low risk where it is possible to make recommendations about adjuvant systemic therapy. For example, outside of clinical trials, it is reasonable not to treat patients with tumors less than or equal to 1 cm in diameter because their chance of recurrence is less than 10 percent at 10 years. With increasing tumor diameter, other prognostic factors should be weighed in the decision to use adjuvant treatment. A major goal is the development of risk profile systems with sufficient accuracy and reproducibility to estimate prognosis in the individual patient.    What Are the Directions for Future Research? To refine existing prognostic factors by: reassessing the predictive value of the tumor categories in the American Joint Committee on Cancer Tumor/Node/Metastasis staging system. standardizing a nuclear grading system. exploring relationships between individual prognostic factors and resistance to systemic therapy. developing and using new and existing tissue and clinical data banks for the study of prognostic factors. To develop risk factor profile systems with sufficient accuracy and reproducibility to allow identification of subgroups that: may be treated with surgical excision without irradiation. do not require axillary node dissection. do not require systemic therapy. To improve systemic chemotherapy regimens through: investigation of dose intensity, timing, and duration. introduction of new agents. evaluation of chemotherapy and hormonal therapy combinations. evaluation of preoperative (neoadjuvant) chemotherapy. To gather further data concerning tamoxifen, including: safety of prolonged use in premenopausal patients. optimal duration of therapy. efficacy in patients with steroid receptor negative tumors. comparison and combination with gonadotropin-releasing hormone agonists. To assess quality-of-life parameters in future clinical trials. To determine the optimal margin for local primary excision in the presence and absence of extensive intraductal cancer. To determine whether boost irradiation is required in patients with pathologically negative margins and whether boost irradiation produces a high probability of local control in patients with microscopic involvement of margins. To determine the optimal sequence and timing for radiation therapy and systemic adjuvant therapy. Conclusions and Recommendations Breast conservation treatment is an appropriate method of primary therapy for the majority of women with Stage I and II breast cancer and is preferable because it provides survival equivalent to total mastectomy and axillary dissection while preserving the breast. The recommended technique for breast conservation includes: local excision of primary tumor with clear margins. Level I-II axillary node dissection. breast irradiation to 4,500-5,000 cGy with or without a boost. The many unanswered questions in the adjuvant systemic treatment of node negative breast cancer make it imperative that all patients who are candidates for clinical trials be offered the opportunity to participate. The majority of patients with node negative breast cancer are cured by breast conservation treatment or total mastectomy and axillary dissection. The rate of local and distant recurrence following local therapy for node negative breast cancer is decreased by both adjuvant combination cytotoxic chemotherapy and by adjuvant tamoxifen. The decision to use adjuvant treatment should follow a thorough discussion with the patient regarding the likely risk of recurrence without adjuvant therapy, the expected reduction in risk with adjuvant therapy, toxicities of therapy, and its impact on quality of life. While all node negative patients have some risk for recurrence, patients with tumors less than or equal to 1 centimeter have an excellent prognosis and do not require adjuvant systemic therapy outside of clinical trials. Consensus Development Panel William C. Wood, M.D. Conference and Panel Chairman Associate Professor of Surgery Harvard Medical School Chief of Surgical Oncology Massachusetts General Hospital Cancer Center Massachusetts General Hospital Boston, Massachusetts Thomas A. Barringer, M.D. Carmel Family Physicians Charlotte, North Carolina John M. Daly, M.D. Jonathan E. Rhoads Professor of Surgery Chief Division of Surgical Oncology University of Pennsylvania Philadelphia, Pennsylvania Mary B. Daly, M.D., Ph.D. Associate Director Cancer Control Science Program Fox Chase Cancer Center Philadelphia, Pennsylvania Francine E. Halberg, M.D. Assistant Professor Department of Radiation Oncology University of California, San Francisco San Francisco, California David Harrington, Ph.D. Associate Professor of Biostatistics Dana Farber Cancer Institute/Harvard School of Public Health Boston, Massachusetts David Christian Hohn, M.D. Associate Professor of Surgery The University of Texas M.D. Anderson Cancer Center Houston, Texas James N. Ingle, M.D. Consultant Division of Medical Oncology Mayo Clinic Associate Professor of Oncology Mayo Medical School Rochester, Minnesota Amy Schiffman Langer, M.B.A. Administrative Director National Alliance of Breast Cancer Organizations (NABCO) New York, New York Brian J. Lewis, M.D. Medical Oncologist The Permanente Medical Group San Francisco, California Judith F. Macon, R.N. Program Coordinator Betty Ford Comprehensive Breast Center at Columbia Hospital for Women Medical Center Washington, D.C. Theodore R. Miller, M.D. Professor of Clinical Anatomical Pathology Vice Chairman, Department of Pathology University of California Medical Center at San Francisco San Francisco, California Larry Norton, M.D. Chief Breast and Gynecological Cancer Medicine Service Memorial Sloan-Kettering Cancer Center New York, New York Joel E. Tepper, M.D. Professor and Chairman Department of Radiation Oncology University of North Carolina School of Medicine Chapel Hill, North Carolina Leslie A. Walton, M.D. Professor Department of Obstetrics and Gynecology Associate Director Division of Gynecologic Oncology University of North Carolina School of Medicine Chapel Hill, North Carolina Speakers Michael Baum, Ch.M., F.R.C.S. "Adjuvant Tamoxifen: Results From the NATO and CRC Trials" Professor of Surgery Institute of Cancer Research Royal Marsden Hospital London ENGLAND Mogens Blichert-Toft "A Danish Randomized Trial Comparing Breast Conservation With Mastectomy in Mammary Carcinoma" Professor Odense University Hospital Odense DENMARK Gianni Bonadonna, M.D. "Milan Adjuvant Chemotherapy Trial for Node Negative Breast Cancer Patients" Director Division of Medical Oncology Istituto Nazionale Tumori Milan ITALY Nancy Brinker "Perspective of the Breast Cancer Patient: Implications for Biomedical Research" Founder Susan G. Komen Foundation Dallas, Texas F. Andrew Dorr, M.D. "Future Issues in Adjuvant Therapy for Patients With Node Negative Breast Cancer" Senior Investigator Cancer Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute National Institutes of Health Bethesda, Maryland Lynn G. Dressler, M.A. "DNA Flow Cytometry Measurements Have Significant Prognostic Impact in the Node Negative Breast Cancer Patient: An Intergroup Study (INT 0076)" Staff Scientist Solid Tumor Facility University of New Mexico Cancer Center Albuquerque, New Mexico Bernard Fisher, M.D. "Breast Conservation Trials of the NSABP" "NSABP B-13: Methotrexate + 5-FU in Women With Estrogen Receptor-Negative, Node Negative Breast Cancer" "NSABP B-14: Tamoxifen Versus Placebo in Women With Estrogen Receptor-Positive, Node Negative Breast Cancer" Distinguished Service Professor Chairman, National Surgical Adjuvant Breast and Bowel Project (NSABP) University of Pittsburgh Pittsburgh, Pennsylvania Edwin R. Fisher, M.D. "Prognostic Factors in NSABP Studies of Women With Node Negative Breast Cancer" Chief Pathologist National Surgical Adjuvant Breast and Bowel Project Director, Institute of Pathology Shadyside Hospital Pittsburgh, Pennsylvania Barbara Fowble, M.D. "Radiotherapeutic Considerations in the Treatment of Primary Breast Cancer" Professor of Radiation Department of Radiation Oncology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Richard D. Gelber, Ph.D. "Reporting and Interpreting Adjuvant Clinical Trials" "Quality of Life in Patients Receiving Adjuvant Therapies" Associate Professor Division of Biostatistics and Epidemiology Harvard Medical School and Dana Farber Cancer Institute Boston, Massachusetts Kennedy Gilchrist, M.D. "Pathology Search for Prognostic Factors in the Intergroup 0011 Trial Population: An Ongoing Effort" Associate Professor Wisconsin Clinical Cancer Center Madison, Wisconsin Eli Glatstein, M.D. "Results of the NCI Early Breast Cancer Trial" Chief Radiation-Oncology Branch National Cancer Institute National Institutes of Health Bethesda, Maryland Aron Goldhirsch, M.D. "International Breast Cancer Study Group Trial of Perioperative Chemotherapy" International Breast Cancer Study Group Ospedale Civico Lugano SWITZERLAND Adrian L. Harris, F.R.C.P., D. Phil. "Epidermal Growth Factor Receptor and Other Oncogenes" Professor Clinical Oncology Unit Imperial Cancer Research Fund and University of Oxford Churchill Hospital Headington, Oxford ENGLAND Jay R. Harris, M.D. "Recurrence in the Breast Following Conservative Surgery and Radiotherapy" Clinical Director Joint Center for Radiation Therapy Harvard Medical School Boston, Massachusetts Bruce E. Hillner, M.D. "A Decision Analytic Model of Adjuvant Therapy for Node Negative Breast Cancer Women" Director of Computer-Based Instruction Assistant Professor of Medicine Division of General Medicine Department of Medicine Medical College of Virginia Virginia Commonwealth University Richmond, Virginia Walter Felix Jungi, M.D. "Swiss Adjuvant Trials in Women With Node Negative Breast Cancer: 14-Year Results" Leitender Arzt, Medizinische Klinik Kantonsspital St. Gallen SWITZERLAND Marsha H. Lampert, P.T. "A Prospective Study Comparing Functional Outcome of the Upper Extremity in Women With Primary Breast Cancer Receiving Modified Radical Mastectomy or Excisional Biopsy and Radiation Therapy" Clinical Coordinator of Physical Therapy Service Department of Rehabilitation National Institutes of Health Bethesda, Maryland Richard G. Margolese, M.D. "Surgical Considerations in Selecting Among the Local Therapy Options" Director of Oncology Jewish General Hospital Herbert Black Professor of Surgery McGill University Montreal, Quebec CANADA William L. McGuire, M.D. "The Relative Value of Tumor Size, Hormone Receptors, Flow Cytometry, HER-2/Neu Oncogene, Cathepsin D, and Stress Response Proteins in Predicting Patient Outcome in Axillary Node Negative Breast Cancer" Professor of Medicine Chief of Medical Oncology University of Texas Health Science Center-San Antonio San Antonio, Texas J. Michael Morrison, M.B., F.R.C.S. "The West Midlands Oncology Association Trial of Adjuvant Chemotherapy for Patients With Node Negative Breast Cancer" Consultant Surgeon Department of Surgery Selly Oak Hospital Birmingham ENGLAND Henning T. Mouridsen, M.D., Ph.D. "Classical Prognostic Factors in Node Negative Patients (The DBCG Experience)" Head, Department of Oncology Finsen Institute Copenhagen DENMARK Gerald Ribeiro, M.D., F.R.C.R. "Christie Hospital Adjuvant Trial" Radiation Therapist and Oncologist Christie Hospital Withington, Manchester ENGLAND Paul Peter Rosen, M.D. "Survival and Prognostic Factors in Node Negative Breast Cancer: Results of Long-Term Followup Studies" Attending Pathologist Memorial Sloan-Kettering Cancer Center New York, New York Wendy S. Schain, Ed.D. "Psychosocial Factors Affecting Treatment Recommendations for Primary Breast Cancer" Psychosocial Director Adult Oncology Memorial Cancer Institute Long Beach, California Helen J. Stewart, M.B., Ch.B., F.R.C.S., F.R.C.R. "The Scottish Adjuvant Tamoxifen Trials" Cancer Research Campaign Life Fellow Scottish Cancer Trials Office (MRC) The Medical School The University of Edinburgh Edinburgh UNITED KINGDOM Ian F. Tannock, M.D., Ph.D. "Use of a Physician-Directed Questionnaire To Define a Consensus About Management of Breast Cancer: Implications for Assessing the Costs and Benefits of Treatment" Professor of Medicine/Medical Biophysics Princess Margaret Hospital Toronto, Ontario CANADA Douglass C. Tormey, M.D., Ph.D. "INT-0011: CMFP Versus Observation in High-Risk Node Negative Breast Cancer Patients" Professor of Human Oncology and Medicine University of Wisconsin Clinical Cancer Center Madison, Wisconsin Johannes Adriaan van Dongen, M.D., Ph.D. "Randomized Clinical Trial To Assess the Value of Breast Conserving Therapy in Stage I and Stage II Breast Cancer; EORTC Trial 10801" Professor of Surgical Oncology University of Amsterdam Head of Department of Surgery The Netherlands Cancer Institute Amsterdam THE NETHERLANDS Umberto Veronesi, M.D. "Breast Conservation Trials of the NCI-Milan" Director General Istituto Nazionale Tumori Milan ITALY Planning Committee F. Andrew Dorr, M.D. Planning Committee Chairman Senior Investigator Cancer Therapy Evaluation Program Division of Cancer Treatment National Cancer Institute National Institutes of Health Bethesda, Maryland Linda W. Blankenbaker Program Analyst Office of Medical Applications of Research National Institutes of Health Bethesda, Maryland James A. Bryan II, M.D., M.P.H. Professor of Medicine University of North Carolina University of North Carolina Hospital Chapel Hill, North Carolina Richard D. Gelber, Ph.D. Associate Professor Division of Biostatistics and Epidemiology Harvard Medical School and Dana Farber Cancer Institute Boston, Massachusetts John H. Glick, M.D. Director University of Pennsylvania Cancer Center Philadelphia, Pennsylvania William H. Hall Director of Communications Office of Medical Applications of Research National Institutes of Health Bethesda, Maryland Allen S. Lichter, M.D. Professor and Chairman Department of Radiation Oncology University of Michigan Medical Center Ann Arbor, Michigan C. Kent Osborne, M.D. Division of Oncology Department of Medicine University of Texas Health Science Center San Antonio, Texas Kara Smigel Science Writer Office of Cancer Communications National Cancer Institute National Institutes of Health Bethesda, Maryland Elliott H. Stonehill, Ph.D. Assistant Director National Cancer Institute National Institutes of Health Bethesda, Maryland Ann D. Thor, M.D. Assistant Professor of Pathology Harvard Medical School Department of Pathology Massachusetts General Hospital Boston, Massachusetts William C. Wood, M.D. Conference and Panel Chairman Associate Professor of Surgery Harvard Medical School Chief of Surgical Oncology Massachusetts General Hospital Cancer Center Massachusetts General Hospital Boston, Massachusetts Conference Sponsors National Cancer Institute Samuel Broder, M.D. Director Office of Medical Applications of Research John H. Ferguson, M.D. Director Supplemental Information for NIH Consensus Statement on Treatment of Early Stage Breast Cancer Since the NIH Consensus Statement on Treatment of Early Stage Breast Cancer was issued, additional information has become available that supplements the original statement. Breast conservation has gained in popularity since 1990 and studies indicate that breast conservation is currently performed in 30-50% of patients with breast cancer nationwide(1). These numbers vary according to the geographic area of the country and according to the type of health care system in which patients are being treated (2,3). Although more information is needed regarding the timing of radiation and adjuvant chemotherapy, several randomized studies have shown that radiation can be safely delayed for several months while chemotherapy is administered without any decrease in survival(4,5,6). Several new studies have been completed since the consensus conference was held. These studies indicate that tamoxifen does result in a survival benefit for women with node-negative, hormone receptor positive breast cancer, regardless of age (7,8,9). Five years appears to be the optimal treatment duration for tamoxifen as shorter durations have proven less effective. Treatment beyond five years in women with node-negative breast cancer does not appear to result in additional benefit, and may even be harmful. Further study is needed to clarify whether tamoxifen should be prolonged beyond five years for women with node-positive breast cancer. Tamoxifen has been associated with an increased incidence of endometrial cancers, about 2 cases for every 1000 women treated per year (10). The endometrial cancers occurred almost exclusively in post-menopausal women but all women receiving this drug should undergo annual pelvic examinations and be monitored carefully for abnormal uterine bleeding. Endometrial biopsies or screening with ultrasound have been used to follow patients on tamoxifen but their effectiveness is unproven. It is clear from the randomized trials however that the benefits of tamoxifen in preventing the recurrence of breast cancer in pre- and post-menopausal women outweigh any detrimental side-effects that may occur. Chemotherapy has also demonstrated a survival benefit in clinical trials in which selected women with node-negative, hormone receptor negative breast cancers were treated (11). While tamoxifen does not appear to be effective in hormone receptor negative tumors, chemotherapy has been shown to add to the beneficial effects of tamoxifen in receptor positive tumors (12). The additional benefit observed from the addition of chemotherapy appears to be greater in younger women (less than 50 years old) than in older women, although all ages showed some improvement. Adjuvant therapy should consist of either combination chemotherapy or tamoxifen (20 mg/day for 5 years), and for some patients both therapies should be administered. A large, randomized trial (NSABP B-20) has compared tamoxifen to tamoxifen and chemotherapy in node-negative, estrogen receptor-positive tumors (13). The results show that chemotherapy does add effectively to the survival benefits seen with tamoxifen alone. Toxicity results from this trial reveal no increase thus far in the number of second primary cancers from the addition of chemotherapy was an increase in the risk of thromboembolism which increased from approximately 2% with tamoxifen alone to about 7% for the combination of tamoxifen and chemotherapy. References: Abrams JS, Phillips PH, Friedman MA. Meeting Highlights: a reappraisal of research results for the local treatment of early stage breast cancer. J Natl Cancer Inst 1995;87:1837-1845. Farrow DC, Hunt WC, Samet JM. Geographic variation in the treatment of localized breast cancer. N Engl J Med 1992;326:1097-2101. Potosky AL, Merrill RM, Riley GF et al. Breast cancer survival and treatment in health maintenance organization and fee-for-service settings. J Natl Cancer Inst 1997;89:1683-91. Recht A, Come SE, Henderson IC, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 1996:334;1356-1361. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxife-nonresponsive tumors:results from NSABP B-15. J Clin Onc 1990:8;1483-1496. Thurlimann B, Senn HJ: The changing approach to the treatment of early breast cancer. N Engl J Med 1996:334;1397-1399. Fisher B, Dignam J, Bryant J et al. 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 1996;88:1529-42. Swedish Breast Cancer Cooperative Group. Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. J Natl Cancer Inst 1996;88:1543-1549. Early Breast Cancer Trialists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339:1-15. Fisher B, Costantino JP, Redmond CK et al. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994;86:527-537. Early Breast Cancer Trailists' Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomized trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992;339: 71-85. Fisher B, Dignam J, Wolmark N et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997 Nov 19;89(22): 1673-1682. Fisher B, Dignam J, Wolmark N et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997 Nov 19;89(22): 1673-1682.

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