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Key Words

Breast cancer, ovarian suppression/ovarian ablation, menopause. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Some women with hormone-sensitive breast cancer are at high risk of relapse, and so receive further treatment after surgery. In this study, radiation therapy designed to suppress ovarian function worked just as well as chemotherapy to help premenopausal women avoid a relapse and to survive. The findings are of limited value, however, because the chemotherapy used in the trial is no longer the standard of care.

Source

Journal of Clinical Oncology, November 1, 2006 (see the journal abstract).
(J Clin Oncol 2006 Nov 1; 31: 4956-62)

Background

After breast cancer surgery, some women who face a higher risk that their cancer will return undergo additional treatment with chemotherapy. If their tumors are “hormone sensitive” (that is, if they grow in response to the hormones estrogen and progesterone), such women may also be advised to take the anti-estrogen drug tamoxifen, or another estrogen suppressor such as the aromatase inhibitors anastrozole (Arimidex®) or raloxifene (Evista®).

Ovaries produce estrogen, so women with hormone-sensitive tumors who have not yet gone through menopause may also be advised either to have their ovaries surgically removed or to induce menopause with radiation therapy or drugs. This approach is known as ovarian suppression or ovarian ablation.

The Study

This multicenter, phase III clinical trial based in Scandinavia involved 762 premenopausal women diagnosed with hormone-sensitive cancer in one breast. The women had had their tumors surgically removed and though none had developed distant metastases, all were at high risk of relapse, either because of the size of their tumor or because it had already spread to one or more nearby lymph nodes.

From January 1990 to May 1998, the women were randomly assigned to receive either radiation therapy to suppress the activity of their ovaries or chemotherapy. The chemotherapy consisted of a combination of three drugs: cyclophosphamide, methotrexate, and fluorouracil (CMF).

CMF was considered the standard of care for breast cancer patients during the trial period. However, in 1998 research showed that CMF was inferior to chemotherapy that included an anthracycline drug, such as doxorubicin (Adriamycin®) and that tamoxifen benefits premenopausal women. The trial stopped enrolling new participants at this time.

The study’s principal investigator was Dr. Bent Edjlertsen, M.D., Ph.D., from Copenhagen University Hospital in Denmark. It is known as the Danish Breast Cancer Cooperative Group (DBCG) Trial 89B.

Results

After a median follow-up period of eight years and six months, researchers found that the rate of relapse was the same for women in both the chemotherapy group and the ovarian suppression group. The risk of death after a median of ten years and six months was slightly greater (11 percent) in the ovarian suppression group, but this result was not statistically significant; that is, it could have occurred by chance.

Side effects in the CMF group were not severe: Fifty-seven percent of patients had low blood counts at least once; 33 percent had moderate or severe nausea and vomiting, and only five percent experienced moderate or severe hair loss.

All but eight ovarian suppression patients stopped menstruation permanently. In the CMF group, about two-thirds of patients were menstruating regularly when the study began; of these, 39 percent eventually stopped menstruating permanently, 37 percent continued or resumed menstruating, and in 24 percent the effect of CMF on menstruation was unclear.

Limitations

Potential limitations of this trial “include the use of a chemotherapy regimen (CMF) that some might consider substandard in the era of taxanes and anthracyclines, [and the] failure to incorporate tamoxifen,” write Antonio C. Wolff, M.D., and Nancy F. Davidson, M.D., of Johns Hopkins University in an accompanying editorial.

They also note that the study was designed to show that ovarian suppression was “not inferior” to the CMF chemotherapy, which is a type of trial design that could require more patients than were enrolled here to produce accurate numbers. This means that CMF could have been more beneficial than the final analysis suggested.

Comments

Jennifer Eng-Wong, M.D., a clinical oncologist in the Center for Cancer Research at the National Cancer Institute, emphasizes that women concerned about sustaining their fertility should realize that CMF can also induce menopause. “We need to follow these patients longer to see what the ultimate impact of CMF was on fertility,” she says, though she too notes that CMF is rarely used with such patients any longer

Wolff and Davidson point out that ovarian suppression could well benefit younger hormone receptor-positive patients who retain ovarian function after chemotherapy. Use of newer hormone-suppressing agents, they write, may produce temporary ovarian suppression, “which could…minimize the long-term health effects of premature menopause.”

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