NIH Panel Sets Standards for Adjuvant Breast Cancer Therapy

BETHESDA—Combination chemotherapy as an adjuvant treatment for breast cancer yields long-term survival benefits and should be offered to patients, even those whose tumors have not spread beyond the breast, according to a consensus panel convened by the National Institutes of Health. The panel also recommended hormone therapy for women whose tumors have hormone receptors, and radiation therapy for women who have had a mastectomy and are at high risk of recurrence.

Women with breast cancer face a growing list of effective options for adjuvant treatment, due to the successful completion of several large, randomized clinical trials, said panel chair Patricia Eifel, MD, of M.D. Anderson Cancer Center.

Since the previous NIH Consensus Development Conference on this topic, held in 1990, more compelling evidence has amassed on the long-term advantage of chemotherapy and the advantages of tamoxifen (Nolvadex) for cancers with estrogen receptors. “The duration of the advantage is maintained for 15 years,” Dr. Eifel said.

NIH Consensus Development Conferences utilize an independent, non-Federal panel to weigh the scientific evidence and establish a consensus. This conference addressed only operable, invasive breast cancer. It did not cover metastatic disease or ductal carcinoma in situ (DCIS). It also focused exclusively on adjuvant treatments.

Very few new prognostic or predictive factors for breast cancer have been validated in the last 10 years. The accepted factors used for selecting adjuvant therapy for breast cancer, the panel said, are age, tumor size, axillary node status, histology, standardized pathologic grade, and hormone-receptor status.

Overexpression of HER-2, p53 status, histologic evidence of vascular invasion, and quantitative parameters of angiogenesis have exciting potential, the panel stated, but their role in patient management is not yet established. Also, the panel said, the clinical significance of sentinel lymph node biopsy and of sensitive assays for micrometastatic disease in nodes or bone marrow remain uncertain.

Adjuvant chemotherapy, with two or more agents, substantially improves long-term relapse-free and overall survival, and should be recommended to the majority of women with localized breast cancer, regardless of nodal, menopausal, or hormone-receptor status, the panel said. Four to six courses appears optimal.

Anthracyclines, such as doxorubicin and epirubicin (Ellence), added to adjuvant chemotherapy regimens result in a small but significant improvement in survival, compared with non-anthracycline-containing regimens. The risk of excessive cardiotoxicity with anthracycline use appears to be limited to women who have significant preexisting heart disease.

The panel stated that all women whose tumors are hormone-receptor positive should receive 5 years of tamoxifen, regardless of their age, menopausal status, tumor size, or nodal status. Tamoxifen therapy has led to substantial reductions in tumor recurrence, second primary breast cancers, and death.

If a woman’s hormone-receptor status is unknown, she should be considered receptor positive and offered tamoxifen. HER-2 status should not influence the decision to recommend hormone therapy.

Women who have undergone mastectomy and who have four or more cancerous lymph nodes or an advanced primary tumor would benefit from postsurgical radiation.

Panel member Carolyn B. Hendricks, MD, a medical oncologist at Suburban Specialty Care Physicians, Bethesda, said that postmastectomy radiation is one area where the panel’s conclusions should change current practice.

The panel also recommended ovarian ablation for premenopausal patients who are hormone-receptor positive. Although it is not frequently used in the United States, ovarian ablation through surgery, radiation to the ovaries, or temporary chemical suppression of ovarian function appears to produce a benefit similar to that of cyclophosphamide, metho-trexate, fluorouracil (CMF) chemotherapy. Combining it with chemotherapy offers no benefit.

Having the option of offering temporary ovarian ablation to young women who look forward to childbearing, is an important step forward, Dr. Hendricks said.

Although few studies have included breast cancer patients age 70 years or older, the panel pointed out that these women frequently have tumors with estrogen-receptor protein and have a high likelihood of response to hormone therapy. They are also likely to experience a survival benefit from chemotherapy, but information on toxicities and the effect of comorbid conditions is unavailable.

Noting that more than half of new breast cancers occur in women 65 years and older, the panel stated that studies addressing the value and tolerance of adjuvant therapies in women over age 70 are urgently needed.

What Not to Offer

The consensus panel also pointed out what clinicians should not be offering to their patients. For example, tamoxifen should not be given to women with hormone-receptor-negative disease. Also, there is no evidence yet that combining hormonal treatments, such as tamoxifen and raloxifene (Evista), is beneficial.

“Taxanes are used more widely than this statement would maybe recommend,” said panel member Walter J. Curran, Jr., MD, professor and chairman, Department of Radiation Oncology, Thomas Jefferson University Hospital.

Although taxanes—paclitaxel (Taxol) and docetaxel (Taxotere)—have demonstrated benefit for metastatic breast cancer, the panel was not convinced of their utility for earlier disease. The panel called the data on taxanes for node-positive breast cancer “inconclusive” and recommended that taxanes not be used in node-negative patients outside of randomized clinical trials.

The decision whether to provide adjuvant therapy for women with node-negative cancers smaller than 1 cm is difficult and should be individualized. Several studies have shown that 8-year survival for these patients is greater than 90%. The small benefits derived from adjuvant therapies should be weighed against potential toxicities.

The panel went further to say that patients with small, node-negative breast cancers with favorable histologic subtypes, such as tubular and mucinous cancers, do very well over the long-term without adjuvant chemotherapy following primary treatment.

As women with breast cancer face more treatment options, decision making becomes a more complex process for patients and their physicians, Dr. Eifel said. The panel recommended the development and evaluation of decision aids and other techniques to improve patients’ involvement and understanding of treatment decisions.

Noting that fewer than 3% of cancer patients are treated in clinical trials, the panel called for improvements in patient and physician participation in prospective randomized studies.

It also recommended trials to (1) better define the risks and benefits of continuing tamoxifen therapy beyond 5 years, (2) gather more data on ovarian ablation, (3) explore the value of combined hormone therapy, and (4) determine whether optimal hormone therapy is equivalent, superior, or additive to chemotherapy in premenopausal women whose tumors express hormone-receptor proteins.

The risks and benefits of new selective estrogen-receptor modulators (SERMs) and aromatase inhibitors in the adjuvant setting should be examined as well.

Current randomized trials of high-dose chemotherapy and of taxanes need to be completed to determine their role in the standard management of breast cancer. The panel recommended further study of therapies considered promising, such as trastuzumab (Herceptin), bisphosphonates, and antiangiogenesis compounds.