NIH Consensus Statement
NIH Consensus StatementVolume 17, Number 4November 1–3, 2000Adjuvant Therapy forBreast CancerNATIONAL INSTITUTES OF HEALTHOffice of the Director
About the NIH Consensus Development ProgramNIH Consensus Development Conferences are convenedto evaluate available scientific information and resolve safetyand efficacy issues related to a biomedical technology. Theresultant NIH Consensus Statements are intended to advanceunderstanding of the technology or issue in question and to beuseful to health professionals and the public.NIH Consensus Statements are prepared by nonadvocate,non-Federal panels of experts, based on (1) presentations by investi gators working in areas relevant to the consensus questions duringa 2-day public session, (2) questions and statements from conferenceattendees during open discussion periods that are part of the publicsession, and (3) closed deliberations by the panel during the remain der of the second day and morning of the third. This statement is anindependent report of the consensus panel and is not a policystatement of the NIH or the Federal Government.Reference InformationFor making bibliographic reference to this consensus statement,it is recommended that the following format be used, with orwithout source abbreviations, but without authorship attribution:Adjuvant Therapy for Breast Cancer. NIH Consensus Statement 2000November 1-3; 17(4): 1-35.Publications Ordering InformationNIH Consensus Statements, NIH Technology AssessmentStatements, and related materials are available by writing tothe NIH Consensus Program Information Center, P.O. Box 2577,Kensington, MD 20891; by calling toll-free 1-888-NIH-CONSENSUS(888-644-2667); or by visiting the NIH Consensus DevelopmentProgram home page at http://consensus.nih.gov on theWorld Wide Web.5
NIH Consensus StatementVolume 17, Number 4November 1–3, 2000Date of original release: November 3, 2000Adjuvant Therapy forBreast CancerThis statement reflects the panel’s assessmentof medical knowledge available at the timethe statement was written. Thus, it providesa “snapshot in time” of the state of knowledgeof the conference topic. When reading thestatement, keep in mind that new knowledgeis inevitably accumulating through medicalresearch.NATIONAL INSTITUTES OF HEALTHOffice of the Director
Disclosure StatementAll of the panelists who participated in this conferenceand contributed to the writing of this consensus statementwere identified as having no financial or scientific conflict ofinterest, and all signed conflict of interest forms attesting tothis fact. Unlike the expert speakers who present scientificdata at the conference, the individuals invited to participateon NIH consensus panels are selected specifically becausethey are not professionally identified with advocacy positionswith respect to the conference topic or with research thatcould be used to answer any of the conference questions.
AbstractObjectiveTo provide health care providers, patients, and the generalpublic with a current consensus on various issues relatedto the use of adjuvant therapy for breast cancer.ParticipantsA nonfederal, nonadvocate, 14-member panel represent ing the fields of oncology, radiology, surgery, pathology,statistics, public health, health policy, and the public; 30experts in medical oncology, molecular oncology, biosta tistics, epidemiology, surgical oncology, and clinical trialswho presented data to the consensus panel; a conferenceaudience of approximately 1,000.EvidenceThe literature was searched using MEDLINE and an exten sive bibliography of references was provided to the panel.Experts prepared abstracts with relevant citations from theliterature. Scientific evidence was given precedence overclinical anecdotal experience.Consensus ProcessThe panel, answering predefined questions, developedtheir conclusions based on the scientific evidence pre sented in open forum and the scientific literature. The panelcomposed a draft statement that was read in its entiretyand circulated to the experts and the audience for comment.Thereafter, the panel resolved conflicting recommendationsand released a revised statement at the end of the conference.The panel finalized the revisions within a few weeks after theconference. The draft statement was made available on theWorld Wide Web immediately following its release at theconference and was updated with the panel’s final revisions.1
ConclusionsDecisions regarding adjuvant hormonal therapy shouldbe based on the presence of hormone receptor proteinin tumor tissues. Adjuvant hormonal therapy should beoffered only to women whose tumors express hormonereceptor protein.Because adjuvant polychemotherapy improves survival,it should be recommended to the majority of women withlocalized breast cancer regardless of nodal, menopausal,or hormone receptor status. The inclusion of anthracyclinesin adjuvant chemotherapy regimens produces a small butstatistically significant improvement in survival over nonanthracycline-containing regimens.Available data are currently inconclusive regarding the useof taxanes in adjuvant treatment of node-positive breastcancer. The use of adjuvant dose-intensive chemotherapyregimens in high-risk breast cancer and of taxanes in nodenegative breast cancer should be restricted to randomizedtrials. Ongoing studies evaluating these treatment strategiesshould be supported to determine if they have a role inadjuvant treatment.Studies to date have included few patients older than70 years. There is a critical need for trials to evaluatethe role of adjuvant chemotherapy in these women.There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy benefit frompostoperative radiotherapy. This high-risk group includeswomen with four or more positive lymph nodes or anadvanced primary cancer. Currently, the role of postmastectomy radiotherapy for patients with one to threepositive lymph nodes remains uncertain and should betested in a randomized controlled trial.Individual patients differ in the importance they place onthe risks and benefits of adjuvant treatments. Quality-of-lifeneeds to be evaluated in selected randomized clinical trials2
to examine the impact of the major acute and long-term sideeffects of adjuvant treatments, particularly premature meno pause, weight gain, mild memory loss, and fatigue. Methodsto support shared decision-making between patients andtheir physicians have been successful in trials; they needto be tailored for diverse populations and should be testedfor broader dissemination.3
IntroductionEach year, more than 180,000 women in the United Statesare diagnosed with breast cancer, the most common typeof noncutaneous cancer among women in this country. Ifcurrent breast cancer rates remain constant, a woman borntoday has a one in ten chance of developing breast cancer.Because of continuing research into new treatment methods,women with breast cancer now have more treatment optionsand a better chance of long-term survival than ever before.The primary treatment of localized breast cancer is eitherbreast-conserving surgery and radiation or mastectomywith or without breast reconstruction. Systemic adjuvanttherapies that are designed to eradicate microscopic de posits of cancer cells that may have spread or metastasizedfrom the primary breast cancer have been demonstratedto increase a woman’s chance of long-term survival.Systemic adjuvant therapies include chemotherapy(anticancer drugs) and hormone therapy. In addition tothese systemic therapies, radiotherapy is used in selectedcases as a local adjuvant treatment to destroy breast can cer cells that remain in the chest wall or regional lymph nodesafter mastectomy.The rapid pace of discovery in this area continues to expandthe knowledge base from which informed treatment decisionscan be made. The purpose of this conference was to establisha consensus regarding the use of adjuvant therapy for breastcancer and to communicate that consensus to clinicians,patients, and the general public. After reading relevantliterature and attending a day and a half of presentationsand audience discussion, an independent, non-Federalconsensus development panel weighed the scientificevidence and drafted a statement that was presented tothe conference audience on the third day. The consensusdevelopment panel’s statement addresses the followingkey questions: Which factors should be used to select systemicadjuvant therapy?4
For which patients should adjuvant hormonal therapybe recommended? For which patients should adjuvant chemotherapybe recommended? Which agents should be used,and at what dose or schedule? For which patients should post-mastectomy radiotherapybe recommended? How do side effects and quality-of-life issues factorinto individual decision-making about adjuvant therapy? What are promising new research directions foradjuvant therapy?This conference was sponsored by the National CancerInstitute and the NIH Office of Medical Applications ofResearch. The co-sponsors included the National Instituteof Nursing Research and the NIH Office of Research onWomen’s Health.5
Which Factors Should Be Used To SelectSystemic Adjuvant Therapy?The selection of systemic adjuvant therapy is based onprognostic and predictive factors. Prognostic factors aremeasurements available at diagnosis or time of surgerythat, in the absence of adjuvant therapy, are associatedwith recurrence rate, death rate, or other clinical outcome.Predictive factors are measurements associated with thedegree of response to a specific therapy. For example,a demonstration of hormone receptors in tumor cellspredicts the response to hormonal therapy. Any factorhas the potential to be both prognostic and predictive,and a factor’s importance depends on both the clinicalendpoint and on the method of treatment comparison.Prognostic and predictive factors fall into three categories:patient characteristics that are independent of the disease(such as age); disease characteristics (such as tumor sizeand histologic type); and biomarkers (measurable param eters in tissues, cells, or fluids), such as hormone receptorstatus, progesterone receptor status, and measures ofcell turnover. Accepted prognostic and predictive factorsinclude age, tumor size, axillary node status, histologicaltumor type, standardized pathologic grade, and hormonalreceptor status.The median age for the diagnosis of breast cancer isbetween the ages of 60 and 65 years. Some youngerwomen (particularly under 35 years) have a more aggressiveform of the disease, characterized by larger tumors of highergrade with vascular invasion. Elderly women (over 70 years)with breast cancer frequently have hormone receptor proteinin their malignant tissue, suggesting a more indolent tumorpattern and a high likelihood of response to hormonal therapy.Race appears to be a prognostic but not predictive factor.In contrast to white women, black breast cancer patientsare generally younger, often have larger tumors at diagnosis,and a smaller percentage have hormone receptors in theirtumor tissue. These factors contribute to a poorer prognosis.In cases of similar clinical presentation, however, adjuvant6
treatment confers similar benefits to black and white women.Research on the benefits and risks of adjuvant therapy inHispanic, Asian, and Native American women is needed.Novel technologies (such as tissue and expression microarrays and proteomics) present exciting potential, but theirintegration into clinical practice will depend on the properdesign and analysis of clinical investigations. The same istrue for overexpression of HER-2/neu, p53 status, histologicevidence of vascular invasion, and quantitative parametersof angiogenesis. These have been extensively studiedclinically and biologically, but do not have an establishedrole in patient management. For example, although over expression/amplification of HER-2/neu is associated withan adverse outcome in node-positive patients and maypredict the response to therapy, laboratory methods andthe reporting of results require standardization before itspredictive performance can be established.The development of immunohistochemical and molecularmethods to identify occult cancer cells (i.e., micrometa stases) in histologically tumor-free axillary lymph nodesor bone marrow has raised questions as to whether suchfindings should alter the clinical stage and become a furtherindication for systemic adjuvant therapy. At present, theclinical significance of these findings remains uncertain,and they require assessment in prospective clinical trialsbefore they directly alter patient management.It is essential that the value of predictive and prognosticfactors be evaluated in well-designed clinical studies thatare based on standardized protocols and have sufficientstatistical power. Because these standards are infrequentlymet, very few new prognostic or predictive factors have beenvalidated in the last 10 years, and future progress will dependon greater attention to these standards. Promising pilotstudies should be followed by a validation phase, duringwhich alternative assays for the biomarker are evaluated ina head-to-head comparison and prognostic/predictive valueis studied. Since no single study will have sufficient powerto properly evaluate predictive value, results from thesetrials should be combined.7
For Which Patients Should AdjuvantHormonal Therapy Be Recommended?The decision whether to recommend adjuvant hormonaltherapy should be based on the presence of hormonereceptors, as assessed by immunohistochemical stainingof breast cancer tissue. If the available tissue is insufficientto determine hormone receptor status, it should be consid ered as being positive, particularly in postmenopausalwomen. The small subset of women whose tumors lackhormone receptor protein but contain progesterone recep tor also appear to benefit from hormonal therapy. Thepresence or absence of HER-2/neu overexpression shouldnot influence the decision to recommend hormonal therapy.The goal of hormonal therapy is to prevent breast cancercells from receiving stimulation from estrogen. Such stim ulation occurs primarily in tumors that contain hormonereceptor protein. Estrogen deprivation can be achievedby (a) blocking the receptor through the use of drugs,such as tamoxifen; (b) suppression of estrogen synthesisthrough the administration of aromatase inhibitors (e.g.,anastrozole) in postmenopausal women or LHRH agonists(e.g., goserelin) in premenopausal women; or (c) destructionof the ovaries through surgery or external beam radiationtherapy. The administration of cytotoxic chemotherapymay indirectly accomplish this same effect by damagingestrogen-producing cells in the ovaries.Adjuvant hormonal therapy should be recommended towomen whose breast tumors contain hormone receptorprotein, regardless of age, menopausal status, involvementof axillary lymph nodes, or tumor size. While the likelihoodof benefit correlates with the amount of hormone receptorprotein in tumor cells, patients with any extent of hormonereceptor in their tumor cells may still benefit from hormonaltherapy. Such treatment has led to substantial reductions inthe likelihood of tumor recurrence, second primary breastcancer, and death persisting for at least 15 years of followup. Possible exceptions to this recommendation include8
premenopausal women with tumors less than 10 mmin size who wish to avoid the symptoms of estrogendeprivation or elderly women with similarly sized cancerswho have a history of venous thromboembolic episodes.Tamoxifen is the most commonly used form of hormonaltherapy. Randomized trials and a meta-analysis haveshown that 5 years of tamoxifen are superior to 1 to 2years of such treatment. Currently, there are no convincingdata that justify the use of tamoxifen for longer than 5 yearsoutside the setting of a clinical trial. Although tamoxifenhas been associated with a slight but definite increasedrisk of endometrial cancer and venous thromboembolism,the benefit of tamoxifen treatment far outweighs its risksin the majority of women. Neither transvaginal ultrasono graphy nor endometrial biopsies are indicated as screeningmaneuvers for endometrial cancer in asymptomatic womentaking tamoxifen. Tamoxifen may be combined with combi nation chemotherapy, particularly in premenopausal women;such combinations may further reduce the risk of recurrence.There are no data to support the use of raloxifene or aroma tase inhibitors as adjuvant hormonal therapy at this time.For hormone receptor positive premenopausal patients,alternative strategies of hormonal therapy, which are usedfar less frequently in the United States, include ovarianablation through surgery, radiation therapy to the ovaries,or chemical suppression of ovarian function. Ovarian ablationappears to produce a similar benefit to some chemotherapyregimens. Combining ovarian ablation with chemotherapyhas not been shown to provide an additional advantage todate. The value of combining hormonal therapies has notyet been adequately explored.Hormonal adjuvant therapy should not be recommendedto women whose breast cancers do not express hormonereceptor protein. Randomized clinical trials have not yetshown that such treatment substantially reduces the likeli hood of recurrence or, in the case of tamoxifen, diminishesthe likelihood of contralateral breast cancer.9
For Which Patients Should AdjuvantChemotherapy Be Recommended?Which Agents Should Be Used, andat What Dose or Schedule?Over the past decade, data have emerged that moreclearly define the subpopulations of women with local ized breast cancer for whom adjuvant chemotherapyis indicated as a standard component of treatment.Chemotherapy has been shown to substantially improvethe long-term, relapse-free, and overall survival in bothpremenopausal and postmenopausal women up to age70 years with node-positive and node-negative disease.Randomized clinical trials have attempted to define opti mal chemotherapy regimens, doses, and schedules inthe adjuvant treatment of breast cancer. These studies,along with the results of overview analyses, permit anumber of conclusions to be drawn.The administration of polychemotherapy ( 2 agents) issuperior to single agents. Four to six courses of treatment(3 to 6 months) appear to provide optimal benefit, with theadministration of additional courses adding to toxicitywithout substantially improving overall outcome. However,definitive data on the benefits of more prolonged treat ment are lacking and future research is needed to directlyaddress this clinically relevant issue.Anthracyclines (such as doxorubicin and epirubicin) havebeen used as components of adjuvant polychemotherapyfor breast cancer. Available data indicate that adjuvantchemotherapy regimens that include an anthracycline resultin a small but statistically significant improvement in survivalcompared to nonanthracycline-containing programs. Thereis no evidence for excessive cardiac toxicity in womenwithout significant preexisting heart disease treated withanthracyclines at the cumulative doses utilized in standardadjuvant programs. In clinical practice, the decision to usean anthracycline in an individual patient should take intoconsideration the potential survival benefits versus specificconcern about additional toxicity.10
Randomized trials have demonstrated threshold doseeffects for two of the most active chemotherapeuticagents, doxorubicin (A) and cyclophosphamide (C). Thesetwo drugs are frequently administered together (AC) andappear to result in a comparable survival outcome, whethergiven preoperatively or postoperatively. However, AC hasnot been compared to cyclophosphamide/doxorubicin/5-fluorouracil (CAF) or cyclophosphamide/epirubicin/5-fluorouracil (CEF). There is a need for future studiesto address the issue of defining the optimal use ofanthracycline-based therapy.There is currently
statement reflects the panel’s assessment of medical knowledge available at the time the statement was written. Thus, it provides a “snapshot in time” of the state of knowledge of the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through
NIH Peer Review Author: Jaya Raman, Ph.D. Subject: NIH Peer Review Presentation Keywords: NIH Peer Review; NIH Peer Review Presentation; Scientific Review Office; NIDCR, NIH; National Instiute of Health; National Insitute of Dental and Craniofacial Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; NICHD;
RESEARCH INSTRUCTIONS FOR NIH AND OTHER PHS AGENCIES . available after announcements through the NIH Guide for Grants and Contracts, a weekly electronic publication that is available on NIH’s Funding page, or additions to the NIH Grants Policy Statement, as needed. R-5.
the magazine. NIH. Medline. Plus A publication of the . Highlights. ON MARCH 14, 2017, FORMER. NIH MEDLINEPLUS. MAGAZINE COVER. celebrity and actress Kathy Bates was honored at a Washington, D.C.-based Research!America awards dinner for her advocacy on behalf of lymphedema and the research of the National Institutes of Health (NIH).
and to review all NIH Toolbox measures as they relate to the needs of young children. NIH TOOLBOX APP Released in 2015, the NIH Toolbox iPad app takes advantage of portable technology and advanced software to provide users with a exible and easy-to-use NIH Toolbox test administration and data collection system. App
Science Conference Statement reflects an independent panel’s assessment of the medical knowledge available at the time the statement is written; as such, it provides a ―snapshot in time‖ of the state of knowledge consensus.nih.govon the conference topic. It is not a policy statement of the NIH or the Federal Government.
National Institute of Child Health and Human Development and the Ofice of Medical Applications of Research of NIH convened a Consensus Development Conference on March 8–10, 2010. The conference was grounded in the view that a thorough evaluation of the relevant research would help pregnant women and their
the magazine 24 a new National library of Medicine exhibition on native peoples includes a hand-built healing totem pole. 10 2 channing o’Halloran is a happy, healthy 9-year-old, thanks to life-sav - ing research at the NiH clinical center. IFC From the FNLM Chairman: 2011 Medical Awards 2 NIH Research: The NIH Clinical Center is America’s .
Released: September 25, 2017 Revised: December 7, 2018 SBIR/STTR INSTRUCTIONS FOR NIH AND OTHER PHS AGENCIES SF424 (R&R) APPLICATION PACKAGES Guidance developed and maintained by NIH for preparing and submitting applications via Grants.gov to NIH and other PHS agencies using the SF424 (R&R)
