Dr. Susan Love Research Foundation | Two New Studies May Change Treatment Options For Premenopausal Women

Two new studies comparing breast cancer treatments may change the current routine use of chemotherapy following surgery in premenopausal women.

Both studies, published in the December 15, 2002, issue of the Journal of Clinical Oncology, were conducted in Europe, where endocrine therapy is already more widely used in the adjuvant setting. Endocrine therapies are treatments that block or alter the hormone levels of estrogen and progesterone, which fuel many breast cancers.

The first of the two studies, the Austrian Breast and Colorectal Cancer Study Group Trial 5, compared the benefits of combination endocrine therapy with standard chemotherapy. Launched in 1990, this study involved 1,034 women whose tumors were estrogen receptor (ER) or progesterone receptor (PR) positive and who had Stage I or Stage II disease.

The women were randomized to receive either combination endocrine treatment or chemotherapy. The women receiving endocrine treatment were given goserelin (brand name Zoladex)—which puts you into temporary menopause—for three years and tamoxifen—which blocks estrogen from getting to the cancer—for five years. The women in the chemotherapy arm received six cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF).

When the trial began it was known that chemotherapy and oophorectomy (surgical removal of the ovaries) were both effective adjuvant treatments for premenopausal women. It was also known that tamoxifen was effective for treating postmenopausal women, whose ovaries have shut down. This led the researchers to hypothesize that giving premenopausal women Zoladex along with tamoxifen would make the tamoxifen more effective. And that is what this study found.

The data collected five years after the study began shows that in the group of women who received endocrine therapy, 17 percent (88) had the cancer come back and 5 percent (24) had a local recurrence in the breast or scar. In contrast, in the group that received CMF, 21 percent (109) had the cancer come back and 8 percent (42) had a local recurrence in the breast or scar. The researchers also reported that in the endocrine therapy group, 3 women developed cancer in the opposite breast, as did 12 women receiving chemotherapy. Eight percent (41) of the women receiving endocrine therapy died compared with 10 percent (51) receiving CMF.

Based on these finding the researchers conclude that "complete endocrine blockade with Zoladex for three years and tamoxifen for five years is superior to standard CMF chemotherapy in the adjuvant treatment of premenopausal women with stage I and II breast cancer."

The second study, conducted by the Zoladex Early Breast Cancer Research Association (ZEBRA), began in 1990. This study enrolled 1,614 premenopausal women with node-positive breast cancer. The women enrolled were both ER-positive and ER-negative because, as the researchers explain, when this trial began treatment decisions were not yet based on ER status.

In this trial women received either Zoladex for two years or six cycles of CMF. The data collected six years after the study began shows that, overall, local and distant recurrences, including contralateral breast cancer, second primary cancers, and deaths were comparable between the two groups. But when the researchers looked at subgroups of ER-positive and ER-negative women, they found that for ER-positive women the chance of recurrence was virtually the same whether they were in the CMF or Zoladex arms, but that for ER-negative women CMF was a better option.

The study results led the researchers to conclude "cytotoxic [chemo] therapy should remain the adjuvant treatment of choice in ER-negative tumors. However, approximately 60 percent of premenopausal women with breast cancer have ER-positive tumors. [Zoladex] offers an effective well-tolerated alternative to CMF in the management of premenopausal patients with ER-positive and node-positive early breast cancer."

Susan says:

In Europe, where medicine is socialized and doctors have the incentive to use the least expensive approach that works the best, endocrine therapy has been much more widely accepted. In the US, where oncologists get paid more by the insurance companies for giving chemotherapy and the pharmaceutical companies are powerful, chemotherapy has been a greater focus of research efforts and is the mainstay of adjuvant treatment for premenopausal women diagnosed with breast cancer. In an editorial accompanying the two studies described above, Kathleeen Pritchard, MD, of the Toronto Sunnybrook Regional Cancer Centre, argues that it may be time for a "paradigm shift" in adjuvant treatment for premenopausal women and notes that based on these and other recent studies "it may well be that a patient who, today, in most of North America would be treated with CMF or an equivalent chemotherapy regimen such as doxorubicin and cyclophosphamide (AC), and who has ER-positive or PR-positive disease, could be equally well treated by a combination of ovarian ablation (by surgical, irradiation or medical suppressive means) plus tamoxifen."

But women in the US may not find their oncologists as open to using endocrine therapy as is Pritchard, a Canadian who practices under socialized medicine. In the US more women receive AC than CMF. And because we don't have any data comparing AC to endocrine therapy, US oncologists are more hesitant to recommend or use Zoladex instead of AC. That's why rather than replacing chemotherapy with endocrine therapy, US oncologists have begun experimenting with a combination of the two. For example, women in the US who have been treated with AC and have not become menopausal are now sometimes offered Zoladex for three years.

I think it's great that studies such as the ones mentioned above are reopening an old debate about the role of amenorrhea—having your periods stop—in breast cancer treatment.

Chemotherapy often causes amenorrhea and studies have found that women whose periods permanently stop have a better prognosis than do those women who get their periods back. (This is also directly linked to a woman's age. Older women are less likely to have their periods return than are younger women.)

Zoladex does not always cause permanent amenorrhea. In the ZEBRA trial, 68 of the 511 women on Zoladex had their periods return after they stopped treatment. However the researchers found that there was no difference in survival between the group of women who got their periods back and those who did not. (This was reported at the 2002 San Antonio Breast Cancer Conference.)

This is important because researchers were concerned that Zoladex was only effective as long as a woman was on it. Instead, it now appears that Zoladex seems to work more like tamoxifen, which puts cancer cells to sleep (or maybe even kills them) and then keeps them asleep even after treatment ends. This finding may lead women to evaluate their options in different ways. For if three years of temporary menopause induced by Zoladex can have the same effect as long-term menopause induced by chemotherapy, Zoladex may be a better quality-of-life choice for some women.

Given the reliance of US oncologists on chemotherapy, it may be some time before women in this country are presented with the options given to women in Europe. The differences between the US and European approaches to breast cancer treatment were especially apparent in recent consensus statements developed by the 2000 United States National Institutes of Health Consensus Development Conference on Adjuvant Therapy for Breast Cancer and the 2001 Seventh International Conference on Adjuvant Therapy of Primary Breast Cancer.

Looking at the exact same data the two groups came to different conclusions on treatment for premenopausal women with hormone receptor-positive tumors. The US consensus panel concluded that adjuvant chemotherapy should be recommended for most women with localized breast cancer and that hormonal therapy should be offered to all women with ER- or PR-positive tumors. In contrast, the international consensus group concluded that "combined tamoxifen and [Zoladex] may be regarded as a proper treatment for premenopausal women with endocrine-responsive disease."

I believe it is long past time for doctors in the US to be more open to endocrine therapies. Oncologists should be telling their patients about these studies and be discussing endocrine therapy as an alternative to chemotherapy as they review treatment options. Women who come in asking for "the most aggressive therapy they can have" may find it hard to believe that endocrine therapy that combines tamoxifen and Zoladex can be as or more effective than chemotherapy, which they are more used to hearing about. But as this research shows, endocrine therapy has much to offer and could benefit many more women in the US than who are currently being offered this option.

References:

Jakesz R, Hausmaninger H, et al. Randomized Adjuvant Trial of Tamoxifen and Goserelin Versus Cyclophosphamide, Methotrexate, and Fluorouracil: Evidence for the Superiority of Treatment with Endocrine Blockade in Premenopausal Patients with Hormone-Responsive Breast Cancer—Austrian Breast and Colorectal Cancer Study Group Trial 5. Journal of Clinical Oncology 2002 Dec 15;20(24):4621–27.

Jonat W, Kaufmann M, et al. Goserelin Versus Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy in Premenopausal Patients with Node-Positive Breast Cancer: The Zoladex Early Breast Cancer Research Association Study. Journal of Clinical Oncology 2002 Dec 15;20(24):4628–35.

Pritchard K. Editorial. Adjuvant Therapy for Premenopausal Women with Breast Cancer: Is It Time for Another Paradigm Shift? Journal of Clinical Oncology 2002 Dec 15;20(24):4611-14.

Davison NE, Levine M. Breast Cancer Consensus Meetings: Vive la Difference? Journal of Clinical Oncology 2002 Apr 1;20(7):1719–20.