The National Institutes of Health (NIH) has released a consensus statement on adjuvant therapy for breast cancer. The statement was prepared by a nonadvocate group of experts who work in the field and is an independent panel report, not an official document of the NIH or the federal government. The panel, chaired by Patricia Eifel, M.D., a professor of radiation oncology at M.D. Anderson Cancer Center in Houston, grew out of a three-day NIH Consensus Development Conference on the topic held in November 2000 in Bethesda, Md. This conference was sponsored by the National Cancer Institute and the NIH Office of Medical Applications of Research. The co-sponsors included the National Institute of Nursing Research and the NIH Office of Research on Women's Health. The complete text of the consensus statement can be found online athttp://consensus.nih.gov.
For the first time, breast cancer rates in the United States are falling, in part because of refinements in adjuvant treatment. However, each year more than 180,000 women are diagnosed with breast cancer. The primary treatment of localized breast cancer is either breast-conserving surgery and radiation, or mastectomy with or without breast reconstruction. Adjuvant therapies administered after surgery eradicate deposits of cancer cells that may have spread from the primary cancer site, and such therapies increase a woman's chance of long-term survival. Retrospective studies report that women may be willing to undergo treatment for as little as a 1 to 2 percent improvement in the probability of survival.
The NIH consensus panel addressed the following questions: Which factors should be used to select systemic adjuvant therapy? For which patients should adjuvant hormone therapy be recommended? Which agents should be used, and at what dose or on what schedule? For which patients should postmastectomy radiotherapy be recommended? How do side effects and quality-of-life issues factor into individual decision making about adjuvant therapy? What are promising new research directions for adjuvant therapy?
To manage women with breast cancer, the panel concluded that treatment with a combination of chemotherapy drugs, particularly combinations that include anthrax cyclines and tamoxifen, provides the best chance for survival. This treatment approach is appropriate for most women with localized breast cancer. Women whose tumors have estrogen receptors should receive hormone therapy, and women who have undergone mastectomies and who are at a high risk for recurrence of cancer should receive radiotherapy. The panel also identified several areas that require more research—notably, research of several drug classes (such as taxanes) is needed, and more women older than 70 years should be included in trials.
Selecting Adjuvant Therapy
The selection of systemic adjuvant therapy is based on prognostic and predictive factors. Prognostic factors are measurements available at diagnosis or at the time of surgery that are associated with recurrence rate, death rate or other clinical outcome when adjuvant therapy is not provided. Predictive factors are measures associated with the response to a specific therapy. Few new prognostic or predictive factors have been validated in the past 10 years.
Patient characteristics must be taken into account when planning therapy. Such characteristics may be independent of the disease (such as age); disease characteristics (such as tumor size and histologic type); and biomarkers, which are measurable parameters in tissues, cells or fluids (such as hormone receptor status, progesterone receptor status and measures of cell turnover). According to the panel, accepted prognostic and predictive factors include age, tumor size, axillary node status, histologic tumor type, standardized pathologic grade and hormone-receptor status.
The age and race of the patient may be used to make generalizations about appropriate care, but adjuvant therapy must always be tailored to the individual woman, her disease and her needs. The median age of a woman diagnosed with breast cancer is 60 to 65 years. Some younger women (particularly those younger than 35 years) have a more aggressive form of the disease, characterized by larger tumors of higher grade with vascular invasion. Elderly women (older than 70 years) with breast cancer frequently have hormone receptor protein in their malignant tissue, which suggests that the cancer may respond to hormone therapy.
Race appears to be a prognostic, but not predictive, factor. In contrast to white women, black patients with breast cancer are generally younger, often have larger tumors at diagnosis and have a smaller percentage of hormone receptors in their tumor tissue. These factors contribute to a poorer prognosis. However, in cases of similar clinical presentation, adjuvant treatment confers similar benefits to black and white women.
Recommending Hormone Therapy
The decision of whether to recommend adjuvant hormone therapy should be based on the presence of hormone receptors, as assessed by immunohistochemical staining of breast cancer tissue. If the available tissue is insufficient to determine hormone receptor status, it should be considered positive. Women whose tumors lack hormone receptor protein but contain progesterone receptor may also benefit from hormone therapy. The NIH consensus panel believes that adjuvant hormone therapy should be recommended to all women whose breast tumors contain hormone receptor protein, but hormone therapy should not be administered to women whose cancer cells do not express hormone receptor protein.
Hormone therapy seeks to prevent breast cancer cells from receiving stimulation from estrogen. Such stimulation occurs primarily in tumors that contain hormone receptor protein, so tumors that contain this protein may respond to hormone therapy. Depriving the breast cancer cells of estrogen may be achieved by blocking the receptor via drugs such as tamoxifen; suppressing estrogen synthesis via aromatase inhibitors such as anastrozole in post-menopausal women, or via luteinizing hormone–release factor agonists such as goserelin in premenopausal women; or destroying the ovaries through surgery or external beam radiation therapy.
The most commonly used hormone therapy is tamoxifen, which may be used alone or in combination therapy. Trials indicate that five years of tamoxifen therapy are superior to one to two years of such treatment. Tamoxifen has been associated with an increased risk of endometrial cancer and venous thromboembolism, but in most women, the benefit of tamoxifen treatment far outweighs its risks.
For premenopausal patients with hormone-receptor–positive tumors, alternative strategies of hormone therapy (used infrequently in the United States) include ovarian ablation through surgery, radiation therapy to the ovaries or chemical suppression of ovarian function. Ovarian ablation appears to produce a similar benefit to some chemotherapy regimens. However, ovarian ablation is associated with the development of premature menopause and symptoms associated with menopause, including osteoporosis.
Chemotherapy has been shown to substantially improve long-term, relapse-free and overall survival in pre-menopausal and postmenopausal women up to the age of 70 years with node-positive and node-negative cancer.
On the basis of available data, the NIH consensus panel indicates that adjuvant chemotherapy regimens that include an anthracycline result in improvement in survival compared with programs that do not contain anthracycline. Trials have demonstrated threshold dose effects for two of the most active chemotherapeutic agents, doxorubicin and cyclophosphamide. These two drugs, which are frequently administered together, appear to result in a comparable survival outcome. They may be administered preoperatively or postoperatively.
Chemotherapy and tamoxifen are additive in their impact on the survival of breast cancer patients. Therefore, most patients with hormone-receptor–positive tumors who are receiving chemotherapy should also receive tamoxifen.
Which women will benefit from chemotherapy? Presently, clinicians offer cytotoxic chemotherapy to most women with lymph node metastases or with primary breast cancers larger than 1 cm in diameter (both node-negative and node-positive cancers). For women with node-negative cancers smaller than 1 cm in diameter, physician and patient should work together to decide if chemotherapy is appropriate. In patients with small, node-negative breast cancers with favorable histologic subtypes, such as tubular and mucinous cancers, adjuvant chemotherapy may not be needed. For women older than 70 years, limited data are available. Toxicity is an issue with this population. In addition, these patients may have existing comorbid medical conditions and may die of causes not related to cancer.
The NIH consensus panel notes that the standard of care for breast conservation includes surgery, then breast radiotherapy. Data suggest that improving tumor control rates in breast cancer by radiotherapy can lead to an improvement in survival. Women who are thought to respond best to radiotherapy include those with four or more positive lymph nodes or an advanced primary tumor (a tumor of 5 cm or more in diameter, or a tumor invading the skin or musculature). Older trials indicated that women who received radiotherapy died of radiation-induced vascular problems; however, newer techniques, for which only preliminary data are available, use lower radiation doses that should reduce this risk. Radiotherapy is associated with an increased risk of arm edema.
Radiotherapy after mastectomy must be coordinated with adjuvant multiagent chemotherapy, hormone therapy, or both. Radiotherapy should not be delivered concurrently with anthracycline chemotherapy and should be delivered within the first six months after the mastectomy is performed.
Side effects of adjuvant therapy for breast cancer must be taken into account when planning therapy. Physicians communicate with their patients through decision aids and patient information materials about the medical condition or procedure, treatment side effects, probabilities associated with health outcomes and impact on quality of life. Patients differ in the importance they place on the risks and benefits of adjuvant treatments.
The side effects of chemotherapy include nausea and vomiting, mucositis, hair loss and neutropenia. These occur in varying degrees in different chemotherapy regimens and resolve after the treatment is completed. The simultaneous combination of chemotherapy plus tamoxifen is associated with an increased risk of thromboembolism when compared with tamoxifen use alone. Other adverse effects include premature menopause, weight gain and fatigue; less common events are mild cognitive problems, treatment-related second malignancies and cardiac disease.
The most common side effects of tamoxifen are hot flushes and vaginal discharge. In addition, its use is associated with a slightly increased risk of endometrial cancer, pulmonary emboli and deep venous thrombosis, particularly in women 50 years of age or older. However, the NIH consensus panel notes that the benefits far outweigh the risks.
The NIH consensus panel statement concludes by summarizing the following points:
Generally accepted prognostic and predictive factors include age, tumor size, lymph node status, histologic tumor type, grade, mitotic rate and hormone receptor status.
Decisions regarding adjuvant hormone therapy should be based on the presence of hormone receptor protein in tumor tissues, with adjuvant hormone therapy offered to women whose tumors express hormone receptor protein.
Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of nodal, menopausal or hormone receptor status.
There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or advanced primary cancer.