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Adjuvant Chemotherapy for Breast Cancer

National Institutes of Health
Consensus Development Conference Statement
September 9-11, 1985

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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 Thus some of the material is likely to be out of date, and at worst simply wrong.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: Adjuvant Chemotherapy for Breast Cancer. NIH Consens Statement 1985 Sep 9-11;5(12):1-19.

For making bibliographic reference to the statement in the electronic form displayed here, it is recommended that the following format be used: Adjuvant Chemotherapy for Breast Cancer. NIH Consens Statement Online 1985 Sep 9-11 [cited year month day];5(12):1-19.

Introduction

In 1985, breast cancer will be diagnosed in approximately 120,000 women; in 90 percent of these women, the disease will apparently be limited to the breast and axillary lymph nodes. Despite advances in early diagnosis and primary treatment with surgery, radiation therapy, or both, more than a third of these patients will develop systemic disease and ultimately die. In the broadest sense, all of these patients are potential candidates for some form of systemic adjuvant therapy.

Adjuvant therapy of breast cancer involves the use of cytotoxic drugs or endocrine therapy after definitive primary therapy. The rationale is to eradicate occult metastatic disease that otherwise would be fatal.

The goal of adjuvant therapy is to significantly prolong survival, while maintaining an acceptable quality of life. Three measures are important in evaluating whether this goal is met by specific treatments:

  1. The effect of therapy on overall survival: The length of time a woman survives following a diagnosis of breast cancer.
  2. The effect of therapy on disease-free survival: The length of time a woman remains free of any recurrence of disease. Prolonged periods of disease-free survival may be advantageous in their own right, since quality of life is likely to be better before than after relapse. There is also some evidence that longer periods of disease-free survival may translate into better overall survival rates.
  3. The effect of therapy on quality of life: In choosing an adjuvant therapy program, potential benefits must be balanced against both short-term and long-term side effects. Also important are the substantial psychological, social, and economic problems women may experience as a result of treatment.

 

An increasing number of important prognostic variables have been identified that define the natural history of breast cancer. These include well-established factors such as histologic status of axillary lymph nodes, primary tumor size, steroid hormone receptors, menopausal status or age, and histopathology. Assessment of cell differentiation and proliferation, which can be determined by newer techniques, may also be significant. The pathologic status of the axillary lymph nodes remains the single most important prognostic variable, and four lymph node categories have been defined (negative, 1-3 positive nodes, 4-9 positive nodes, 10 or more positive nodes). Since definitions of menopausal status vary widely among clinical trials, age (<50 versus greater than or equal to 50 years) can be substituted as a prognostic variable.

Current adjuvant therapy trials prospectively stratify patients for certain of these prognostic factors, including lymph node status, menopausal status or age, and hormone receptor levels. Variations in local-regional therapy (mastectomy versus conservative surgery plus radiotherapy) may also be important, as less radical surgery is increasingly employed. However, data pertaining to adjuvant therapy have been obtained almost exclusively in patients following mastectomy.

Gains from new or modified adjuvant regimens must be assessed in unbiased prospective clinical trials in which patients are randomly assigned to alternative treatments. In evaluating the results from these studies, it should be recognized that moderate effects on survival may produce significant public health benefits because of the large number of women who may be affected. These effects may be difficult to detect in individual studies due to the limited number of enrolled patients. It is especially difficult to evaluate modest gains that are restricted to subgroups of patients. For this reason, results must be confirmed in multiple studies so that there is consistency in the findings before any therapeutic regimen becomes accepted as standard care.

Advances in adjuvant therapy have come from the combined efforts of health care professionals and thousands of women who have agreed to participate in clinical trials. Since the vast majority of women with breast cancer are not treated in such trials, recommendations regarding the effectiveness of current treatment regimens must be based on periodic interpretations of the available research data.

At the previous
Consensus Development Conference held in 1980, a significant benefit of adjuvant chemotherapy on overall survival and disease-free survival could be demonstrated only for premenopausal patients with positive axillary lymph nodes. Since the previous conference, a substantial number of new trials have been initiated, and followup in the older trials has continued. This has resulted in the accumulation of new information regarding the role of adjuvant therapy in the treatment of breast cancer.

To evaluate this new information and to resolve some of these questions, the National Institutes of Health convened a
Consensus Development Conference on Adjuvant Chemotherapy for Breast Cancer on September 9-11, 1985.

After listening to a series of presentations by experts in the relevant basic and clinical science areas, a consensus panel composed of representatives from the fields of medical oncology, surgery, radiation therapy, pathology, nursing, epidemiology, biostatistics, family medicine, and the general public considered all of the material presented and agreed on answers to the following questions:

  • Have adjuvant chemotherapy trials in breast cancer demonstrated an increase in survival in any group of patients?
  • What is the role of endocrine treatment in the adjuvant therapy of breast cancer?
  • When should women with histologically negative axillary lymph nodes receive adjuvant therapy?
  • Are there significant adverse effects of adjuvant therapy?
  • What directions for future research are indicated?
Have Adjuvant Chemotherapy Trials in Breast Cancer Demonstrated an Increase in Survival in Any Group of Patients?

Premenopausal

Adjuvant chemotherapy has demonstrated a highly significant increase in disease-free survival and a significant reduction in mortality in premenopausal women with histologically positive axillary lymph nodes. Adjuvant chemotherapy can now be considered standard care for these patients. However, while survival advantages are evident, they remain far from ideal, and improvement in the effectiveness of chemotherapy is a goal that must be given highest priority.

Numerous studies have shown that combination chemotherapy is superior to single-agent treatment. Single-agent chemotherapy should be avoided outside a clinical trial. The optimal drug combination has not been defined and is currently the subject of clinical investigation. For patients who do not have access to or who are ineligible for an investigational protocol, the adjuvant chemotherapy combination selected should be one that has demonstrated efficacy in major clinical trials, and the protocol regimen should be followed in detail. Arbitrary dose reductions to circumvent moderate and manageable toxicity may reduce the effectiveness of adjuvant treatment and should not be made.

An optimal duration of adjuvant chemotherapy has not been defined. Some clinical trials have demonstrated that a duration of more than 1 year is not indicated. Regimens of shorter duration (e.g., 6 months) may be equally effective. When primary breast cancer is managed by conservative surgery and irradiation, full doses of adjuvant chemotherapy should be administered.

Postmenopausal

The efficacy of adjuvant chemotherapy for postmenopausal women is less well established. Many adjuvant chemotherapy trials have failed to show an increase in overall survival for postmenopausal patients with histologically positive axillary lymph nodes. However, in a series of trials from one major cooperative group, a modest increase in disease- free and overall survival has been observed. When the sum of the evidence from all randomized trials is examined, the estimate of increase in disease-free and overall survival is small but statistically significant.

Faced with these data, what recommendations can be made for the treatment of postmenopausal, node positive patients? First, survival advantages that accrue from current adjuvant chemotherapy programs must be improved upon through careful clinical research, and when possible, all patients should be offered entry into such trials. If a clinical trial is not available or the patient is ineligible or refuses to participate, the therapeutic decision must balance the toxicity and cost of treatment against its expected benefit. For the woman with both positive nodes and positive hormone receptor levels, this choice is relatively straightforward; tamoxifen has proven effectiveness and minimal toxicity (see question #2). Thus, outside a clinical trial, tamoxifen is preferred in this subset of patients. For patients with positive nodes but negative hormone receptors, the choice is difficult. For some patients and physicians, a small advantage in disease-free and overall survival balanced against toxicity may be worthwhile. In this situation, adjuvant chemotherapy is appropriate, especially if the woman has four or more positive axillary nodes.

When chemotherapy is used in postmenopausal women, the same principles of dose intensity and duration as discussed above for premenopausal women apply.  

What Is the Role of Endocrine Treatment in the Adjuvant Therapy of Breast Cancer?

Decisions regarding adjuvant endocrine therapy should be made with the knowledge of estrogen and progesterone receptor measurements on the primary tumor. Most studies of primary and metastatic breast cancer indicate that the effectiveness of endocrine therapy closely correlates with measured receptor levels. This justifies the use of receptor information in making decisions regarding adjuvant therapy.

Premenopausal

Adjuvant endocrine therapy, either alone or in combination with cytotoxic chemotherapy, has not been shown to result in a survival benefit for premenopausal patients with positive axillary lymph nodes. Thus, there is no justification for the routine use of adjuvant ovarian ablation or tamoxifen in premenopausal patients outside a clinical trial. However, selected studies indicate that either ovarian ablation or tamoxifen may produce therapeutic benefits that justify further clinical investigation. Trials of adjuvant chemotherapy alone versus chemotherapy plus hormonal manipulation are in progress.

Postmenopausal

In postmenopausal patients with hormone receptor positive tumors and positive axillary nodes, numerous studies have demonstrated a highly significant benefit of tamoxifen on disease-free survival. Most of these individual trials have not yet demonstrated a statistically significant increase in survival, but with limited followup time, the trends are in this direction. An overview of all randomized tamoxifen trials shows a highly significant and substantial improvement in overall survival. This benefit of tamoxifen for women older than 50 years of age is even more important because it can be achieved without serious short-term toxicity. Tamoxifen should now be regarded as standard therapy for postmenopausal patients with positive axillary lymph nodes and positive hormone receptor status.

Adjuvant tamoxifen in patients with negative estrogen receptors is generally regarded as ineffective, and a large cooperative group trial in the United States has verified this point. However, data from some European centers suggest that the effects of tamoxifen in patients with negative estrogen receptors may be worthy of further investigation.

The optimal duration of tamoxifen therapy remains to be defined. However, it appears that a longer duration of adjuvant tamoxifen (e.g., at least 2 years) may be more effective than 1 year. Current trials are evaluating the role of tamoxifen given for 4 or more years. There is no evidence to suggest that a dose of tamoxifen higher than 20 mg per day is indicated.

The therapeutic benefit of tamoxifen may correlate with increasing quantity of hormone receptors, but further investigation of this is required. Additionally, tamoxifen may have its greatest benefit in patients with four or more positive nodes. The role of tamoxifen combined with cytotoxic chemotherapy compared with tamoxifen alone for patients with positive axillary lymph nodes and positive hormone receptors remains unresolved and is the subject of current clinical investigation.  

When Should Women With Histologically Negative Axillary Lymph Nodes Receive Adjuvant Therapy?

Routine administration of adjuvant systemic therapy in women with histologically negative axillary lymph nodes is not recommended at the present time. Unlike some of the other issues addressed in this consensus statement, little progress has been made in this area since the prior consensus meeting. At present, there is not adequate information from randomized clinical trials of adjuvant therapy to demonstrate a significant overall survival benefit for women with negative nodes. Women with negative nodes are encouraged to participate in randomized clinical trials comparing observation with adjuvant therapy.

The prognosis for women with negative axillary lymph nodes is relatively good (65 to 80 percent alive at 10 years). However, some patients with negative nodes are at increased risk for relapse. They may be identified by large tumor size, negative hormone receptors, and cell differentiation pattern, including high degree of anaplasia, high thymidine labeling index, and aneuploidy. For patients at high risk who cannot be entered into an ongoing trial, chemotherapy should be considered, but the decision to institute adjuvant therapy rests with each individual patient and her physician.  

Are There Significant Adverse Effects of Adjuvant Therapy?

The acute toxicity from adjuvant chemotherapy is well known and includes varying degrees of leukopenia, nausea and vomiting, fatigue, and hair loss. Amenorrhea and menopausal symptoms frequently occur as a result of cytotoxic therapy and are rarely reversible in women over 40 years of age. Weight gain during treatment is a troublesome effect reported by many women, especially when regimens containing prednisone are used. The acute physical side effects of chemotherapy may be severe, but most can be effectively mitigated. These effects seldom result in hospitalization, and early treatment-related deaths are rare. The psychological, social, and economic costs are significant for the individual patient and her family. Quantitative studies of these issues should be a high priority in future clinical trials.

Major long-term toxicity from chemotherapy is extremely uncommon, although few studies have followed large numbers of patients for long periods of time. In studies from one group at 10 years' followup, 1.7 percent of women who received phenylalanine mustard for 2 years as part of their chemotherapy regimen developed leukemia or a myeloproliferative syndrome (MPS). This compares with a 0.3 percent cumulative incidence of leukemia or MPS for breast cancer patients in the same studies who did not receive chemotherapy. To date, the use of other alkylating agents (e.g., cyclophosphamide) has not resulted in an increased incidence of leukemia. There is, as yet, no evidence of any greater risk for the development of second solid tumors in patients receiving adjuvant chemotherapy.

Tamoxifen is extremely well tolerated by patients. Side effects, including hot flashes and vaginal dryness, are common and are related to estrogen deprivation. Potential long-term toxicity of tamoxifen is unknown at this time but appears negligible in studies with followup data up to 8 years.

The overall gains in survival achieved by established adjuvant therapy programs for breast cancer significantly outweigh the risk of serious toxicity. Each woman and her physician will need to evaluate the significance of the known and potential side effects of particular regimens when making decisions about the risk-benefit ratio of a specific approach.  

What Directions for Future Research Are Indicated?

Many issues regarding the use of adjuvant cytotoxic and hormonal therapy of breast cancer remain unresolved. Some are best studied by prospective clinical trials; others require basic research in such disciplines as molecular biology, pathology, pharmacology, human genetics, and cell biology. Issues requiring controlled clinical trials include:

  1. Refinement of staging and prognostic subgroups.
  2. Efficacy of adjuvant chemotherapy and/or endocrine therapy in patients with negative axillary lymph nodes.
  3. Innovative and more effective chemotherapy programs for node positive patients: dose intensification, new combinations of drugs to overcome tumor resistance, timing and scheduling of cytotoxic drugs and hormones, including pre- and perioperative treatment.
  4. Optimal duration of tamoxifen administration.
  5. Accurate assessment of the psychological, social, and economic impact of adjuvant therapy.
  6. Methods to better control the short-term side effects of adjuvant therapy.
  7. Continued assessment of the late effects of adjuvant therapy.
 

Conclusions

Adjuvant chemotherapy and hormonal therapy are effective treatments for breast cancer patients. While significant advances have been made in the past 5 years, optimal therapy has not been defined for any subset of patients. For this reason, all patients and their physicians are strongly encouraged to participate in controlled clinical trials.

Outside the context of a clinical trial and based on the research data presented at the 1985
Consensus Development Conference, the following statements can be made:

  • For premenopausal women with positive nodes, regardless of hormone receptor status, treatment with established combination chemotherapy should become standard care.
  • For premenopausal patients with negative nodes, adjuvant therapy is not generally recommended. For certain high-risk patients in this group, adjuvant chemotherapy should be considered.
  • For postmenopausal women with positive nodes and positive hormone receptor levels, tamoxifen is the treatment of choice.
  • For postmenopausal women with positive nodes and negative hormone receptor levels, chemotherapy may be considered but cannot be recommended as standard practice.
  • For postmenopausal women with negative nodes, regardless of hormone receptor levels, there is no indication for routine adjuvant treatment. For certain high-risk patients in this group, adjuvant therapy may be considered.
 

Consensus Development Panel

John H. Glick, M.D.
Panel and Conference Chairman
Professor of Medicine and Director
University of Pennsylvania Cancer Center
Philadelphia, Pennsylvania
Martin D. Abeloff, M.D.
Chief of Medical Oncology
Johns Hopkins Oncology Center
Baltimore, Maryland
Byron Wm. Brown, Jr., Ph.D.
Professor and Head
Division of Biostatistics
Department of Family, Community, and Preventive Medicine
Stanford University School of Medicine
Stanford, California
Charles D. Cobau, M.D.
Associate Clinical Professor of Medicine
Medical College of Ohio at Toledo
Toledo, Ohio
Bonny Libbey Johnson, R.N., M.S.N.
Consultant
West Hartford, Connecticut
Allen S. Lichter, M.D.
Associate Professor and Chairman
Department of Radiation Therapy
University of Michigan Medical Center
Ann Arbor, Michigan
Helen B. O'Bannon
Senior Vice President
University of Pennsylvania
Philadelphia, Pennsylvania
Ruth Ottman, Ph.D.
Assistant Professor of Public Health (Epidemiology)
Sergievsky Center
Columbia University
New York, New York
Jose Russo, M.D.
Chairman
Department of Pathology
Director
Pathology Reference Laboratory
Michigan Cancer Foundation
Detroit, Michigan
Karl Singer, M.D.
Exeter Family Medicine Associates
Exeter, New Hampshire
Abigail Trafford
Assistant Managing Editor
U.S. News & World Report
Washington, D.C.
William C. Wood, M.D.
Director
Massachusetts General Hospital Cancer Center
Harvard Medical School
Boston, Massachusetts

Planning Committee

Marc E. Lippman, M.D. (Chairman)
Head, Medical Breast Cancer Section
Medicine Branch
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Michael J. Bernstein
Director of Communications
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland
George P. Canellos, M.D.
Professor of Medicine
Harvard Medical School
Chief
Division of Medical Oncology
Dana Farber Cancer Institute
Boston, Massachusetts
Joyce Doherty
Information Specialist
Office of Cancer Communications
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Jerry Elliott
Program Analyst
Office of Medical Applications of Research
National Institutes of Health
Bethesda, Maryland
John H. Glick, M.D.
Professor of Medicine and Director
University of Pennsylvania Cancer Center
Philadelphia, Pennsylvania
Brian J. Lewis, M.D.
Associate Clinical Professor of Medicine
University of California, San Francisco
San Francisco, California
Franco M. Muggia, M.D.
Director
Division of Oncology
Professor of Medicine
New York University Medical Center
New York, New York
Robert E. Wittes, M.D.
Associate Director
Cancer Therapy Evaluation Program
Division of Cancer Treatment
National Cancer Institute
National Institutes of Health
Bethesda, Maryland

Conference Sponsors

National Cancer Institute
Vincent T. DeVita, Jr., M.D.
Director
Office of Medical Applications of Research, NIH
Itzhak Jacoby, Ph.D.
Acting Director

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