Adjuvant Chemotherapy for Breast Cancer National Institutes of Health
Consensus Development Conference Statement
July 14-16, 1980
Please see more recent conference statement
Adjuvant Therapy for Breast Cancer published in 2000.
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 Thus some of the material is likely to be out of date, and at worst simply wrong.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 1980 Jul 14-16;3(3):1-4.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 1980 Jul 14-16 [cited year month day];3(3):1-4.
A Adjuvant Chemotherapy of Breast Cancer was held at the National Institutes of Health on July 14-16, 1980. Its purpose was to bring together practicing physicians, research scientists, consumers and others in an effort to reach general agreement on the concepts and results of adjuvant chemotherapy trials in breast cancer and their implications for medical practice.
A consensus development panel and members of the audience considered evidence presented on the following questions:
- Have clinical trials established the efficacy of adjuvant chemotherapy of breast cancer?
- Do the benefits of adjuvant chemotherapy clearly outweigh the risks?
- Should future adjuvant chemotherapy studies include hormonal manipulations?
- What is the role of adjuvant chemotherapy in Stage I patients?
- What is the role of adjuvant chemotherapy in post-menopausal patients?
The members of the panel included a patient and representatives from the many disciplines involved in the evaluation and treatment of breast cancer. The panel met following formal presentations and discussions to assess the issues based on the evidence presented. This summary is the result of its deliberations.
Adjuvant chemotherapy of breast cancer means the use of cytotoxic drugs after primary therapy. The rationale for adjuvant chemotherapy is to eradicate occult metastatic disease which otherwise would be fatal.
The assessment of adjuvant chemotherapy must balance efficacy against toxicity. The basic measure of therapeutic benefit is patient survival with acceptable quality of life.
Primary breast cancer is a heterogeneous disease with varying potentials for metastatic relapse and response to adjunctive drug therapy. Currently, three critical variables are used in planning adjuvant chemotherapy trials: Involvement of the axillary lymph nodes, menopausal status and estrogen receptor levels. Three axillary lymph node categories are commonly accepted as prognostically important: negative axillary nodes, one to three positive axillary nodes and four or more positive nodes. These three categories strongly predict the risk of relapse after appropriate local treatment.
These three nodal subsets, when combined with the menopausal status (pre- or post-) and estrogen receptor (ER) status (positive or negative), result in 12 prognostic subsets. These subsets form the basis for planning additional clinical trials, and it is only from these trials that the best strategy for improved patient care will emerge. Adequate analysis of an adjuvant chemotherapy trial must consider whether enough data exist for one or more subsets to establish the role of that trial in assessing--and possibly modifying--current medical practice.
In general, the merits of a new or modified adjuvant treatment regimen must be assessed through comparative clinical trials, which randomly assign patients to alternative treatments. Such a study design helps assure that patients in each of the treatment groups are comparable.
If a clinical trial is to yield meaningful information, patients need to be followed for a sufficient period, so that long-term results may be evaluated. No simple standard for duration of followup can be set, because the importance of observed results depends on the nature of the patient group under study. For example, in order to provide meaningful information, patients with minimal, potentially curable disease have to be followed for a much longer time than do patients with advanced disease.
There are two types of toxicity associated with chemotherapy: acute and remote. The acute adverse effects relate to the immediate drug administration; remote adverse effects, which also can be chronic, can occur long after drug administration has ceased. Acute toxicities include bone marrow suppression, nausea and vomiting, loss of appetite, weakness, mouth ulcers and hair loss. The remote chronic effects to which the physician should be alerted include organ damage, such as Adriamycin-induced cardiomyopathy, sterility and the induction of second cancers due to the carcinogenic potential of some of the drugs used.
The length of time during which the patient is free of disease after treatment is important but frequently must be regarded as a preliminary indication of therapeutic results. The ultimate efficacy of treatment must be measured in terms of survival time, although the quality of survival must be taken into consideration.
Studies that report negative results, i.e., no significant differences, should not be regarded as failures. If the study initially posed important question(s), and the study was designed and executed properly, then any negative finding is an important contribution to knowledge.
It is desirable to examine the possible influences on therapeutic results by factors not anticipated in the original study design. However, a cautionary note is in order: retrospective observations based on small subgroups of patients may be misleading.
By definition, adjuvant chemotherapy is drug treatment added to adequate local excisional therapy. The adjuvant chemotherapy trials reported to date have employed radical or modified radical mastectomy. Future trials may involve lesser surgical procedures, but the impact of lesser surgery on adjuvant chemotherapy remains to be determined.
In breast cancer treatment, a key prognostic determinant for the use of adjunctive therapies and their results is the status of the axillary lymph nodes at the time of primary therapy. A satisfactory dissection of the axillary nodes and histopathologic evaluation is essential for accurate staging.
With these precepts underlying their discussions, the panel addressed the questions in its charge and came to the following consensus.
Have Clinical Trials Established the Efficacy of Adjuvant Chemotherapy of Breast Cancer?
Despite positive and encouraging findings from clinical trials, the answer to this question must be qualified at this time. The value of adjuvant chemotherapy, in terms of demonstrated increase in survival of treated patients, has been established with any degree of certainty only for a select group of breast cancer patients.
Pre-menopausal patients with histologic evidence of lymph nodal metastases who have undergone local therapy by mastectomy have experienced an increase in disease-free and overall survival after adjuvant chemotherapy with established combination regimens. Adjuvant chemotherapy now appears indicated for this defined subset of breast cancer patients.
Since the optimal adjuvant therapy for the pre-menopausal patient with lymph nodal metastases has not yet been developed, continued clinical investigations are indicated. If entry into a well-planned clinical trial is not feasible or acceptable to patients in this specific group, adjuvant combination therapy is indicated. Regimens which have proven efficacious in recognized clinical trials should be selected. It is the responsibility of the treating physician to evaluate the results of these trials for efficacy and toxicity.
Adjuvant combination chemotherapy, with agents shown to be active in the treatment of advanced breast cancer, has been shown to be more effective than chemotherapy with a single agent. Current information suggests that these drugs should be given at full dosage and for prescribed durations, since lesser amounts of chemotherapy or changes in schedule have shown inferior results.
In combination with adjuvant chemotherapy the Stage II disease, adjuvant radiotherapy has not provided significant increases in survival, although it has reduced chest wall and regional lymph node recurrence in some studies.
Do the Benefits of Adjuvant Chemotherapy Clearly Outweigh the Risks?
Various forms of early toxicity have been documented in regimens that have proven to be therapeutically effective. Late effects of the various drug programs have not been identified fully. The survival benefits in pre-menopausal patients with histologic evidence of lymph node metastases (Stage II) appear to outweigh the disadvantages of early toxicity.
Psychological and socioeconomic problems resulting from adjuvant chemotherapy have been identified as risks, in addition to the direct toxic effects of drugs, but they have not been quantitatively defined. In the meantime, education, counseling and emotional support of the patient by the cancer treatment team are of utmost importance. Increased financial burden to the patient, interruptions in family life and occupation, and changes in image may accompany the use of chemotherapy. This panel believes that these problems should be investigated prospectively and addressed directly in future conferences.
Should Future Adjuvant Studies Include Hormonal Manipulations?
Studies of hormonal manipulation as adjuvant therapy for breast cancer have shown suggestive benefits, but are not definitive when judged in terms of survival. Current studies on estrogen receptor status are yielding more reliable data on the value of hormonal manipulation in the adjuvant setting. The problems that exist in the assessment of these current data include determination of the relative roles of hormonal and chemotherapeutic treatments, significance of the hormonal effects of the chemotherapeutic agents and reliability of the receptor assays in individual patients.
For now, it appears that no hormonal manipulation has been established with enough confidence to make hormonal alterations--either alone or with chemotherapy--a standard form of adjuvant therapy. Recent data regarding potential benefits for hormonal treatment in patients demonstrating significant estrogen receptor activity are encouraging.
ER activity should be quantified routinely in all patients with breast cancer. In all adjuvant trials, particularly those involving the use of hormonal treatment, ER activity is an essential factor for the classification of patients in planning the design of the clinical trial.
What Is the Role of Adjuvant Chemotherapy in Stage I Patients?
Patients with histopathologically negative axillary lymph nodes have a good prognosis after appropriate local therapy. The 5-year disease-free survival without adjuvant chemotherapy can be expected to be at least 80 percent. The use of adjuvant chemotherapy in Stage I patients exposes all to risks of toxicity without possible benefit to the majority. Some relevant studies are underway, but no conclusive data from clinical research exist to support the routine use of adjuvant chemotherapy in this situation. Clinical research is now in progress to determine whether it is possible to identify a subset of patients with negative axillary nodes who are at high risk of relapse after primary therapy.
What Is the Role of Adjuvant Chemotherapy in Post-Menopausal Patients?
Recent analyses of some ongoing adjuvant chemotherapy studies seem to show early benefit in disease-free survival in one or more subsets of post-menopausal patients with positive axillary nodes. The preliminary nature of this information precludes a definitive statement as to the role of such treatment. Clinical investigations should continue to explore the role of adjuvant chemotherapy in post-menopausal women with positive axillary nodes. Broad acceptance of the results of such trials would require concurrent controls, receiving only surgical treatment. Post-menopausal women with ER-positive tumors may benefit from the adjuvant administration of relatively non-toxic hormonal treatment in combination with cytotoxic drugs. It appears logical that hormonal therapy and chemotherapy should continue to be explored in ER-positive post-menopausal women, but only within the setting of well-controlled clinical trials.
Current information indicates that it might be necessary to give multiple drug regimens at full dose to achieve clinical benefit. Retrospective evaluation of patients in one large trial now seems to show survival benefit for those post-menopausal patients who ultimately receive the maximum prescribed dosage in contrast to those who receive lower dosage.
Adjuvant chemotherapy of breast cancer is a rapidly changing and progressing field. New concepts have emerged from large, complex clinical trials. But women with breast cancer and physicians need to understand that definitive answers do not exist for the best management of all aspects of this complex disease. The optimal approach to decision-making and treatment is multi-disciplinary, within the framework of knowledge provided by current research. Because these drugs are toxic, administration of chemotherapy should be undertaken only by or under the supervision of a physician experienced in their use. Optimal care requires frank and open communication between the physician and patient about the options available and the variables which make up the patient's potential prognosis, both for the risk of relapse and for response to therapy.
Stephen K. Carter, M.D.
Northern California Cancer Program
Palo Alto, California
George P. Canellos, M.D.
Sidney Farber Cancer Institute
Barbara E.F. Chambers
Sidney J. Cutler, Sc.D.
Edwin R. Fisher, M.D.
University of Pittsburgh
Robert W. Frelick, M.D.
Association of Community Cancer Centers
Walter Lawrence, Jr., M.D.
Chairman, Commission on Cancer
American College of Surgeons
Theodore L. Phillips, M.D.
University of California Medical Center
San Francisco, California
Hiram C. Polk, Jr., M.D.
University of Louisville
Health Sciences Center
Connie Kenke Yarbro, R.N.
Oncology Nursing Society
National Cancer Institute
Daniel G. Haller, M.D. (Program Coordinator)
Office of Medical Applications of Research