Patients with estrogen receptor-positive cancers often experience treatment responses to a number of hormonal therapies, and the optimal sequence of agents has changed as new endocrine interventions have been evaluated. In premenopausal women, tamoxifen and ovarian ablation/suppression seem to be equivalent alternatives as first-line therapy, and some evidence supports the use of the combination. In postmenopausal women, third-generation aromatase inhibitors have emerged as a viable alternative to tamoxifen, and are often given as first-line therapy. Recent clinical trial data comparing the estrogen receptor downregulator fulvestrant to anastrozole suggests at least equal – and perhaps greater – efficacy as second-line therapy after tamoxifen. Fulvestrant is administered as an intramuscular injection, and the integration of this unique endocrine intervention into the algorithm for management of postmenopausal patients will be a key issue in coming weeks when this agent becomes available in a nonprotocol setting.

NCCN GUIDELINES FOR FIRST-LINE HORMONAL THERAPY OF METASTATIC BREAST DISEASE

The non-steroidal aromatase inhibitors are superior to tamoxifen as first-line treatment in metastatic disease. In the current NCCN guideline, the use of aromatase inhibitors has been moved forward to a first-line option for postmenopausal women with hormone – responsive breast cancer. Tamoxifen also remains a first-line option. The non-steroidal aromatase inhibitors – anastrozole and letrozole – are considered equivalent according to the guidelines. Although I have no criticism of practitioners who prefer letrozole, I tend to use anastrozole. It was the first of the selective aromatase inhibitors available. It’s one that I became very comfortable with. I personally use anastrozole almost exclusively in my practice.

—Robert W Carlson, MD

SECOND-LINE TRIALS OF FULVESTRANT VERSUS ANASTROZOLE

The results of the European trial and the American trial show similar response rates between the two drugs, but in the American trial the response duration is about twice as long for fulvestrant compared to anastrozole. Aromatase inhibitors are very good agents. In one of these new trials, fulvestrant is at least as good as anastrozole. In the other trial, we see an advantage at least in one important parameter.

—C Kent Osborne, MD

INTRAMUSCULAR INJECTION

Coming in every month and getting the injection is not a big problem. It’s a 5 cc injection, which for some reason terrorized everybody in the beginning, and initially we actually gave it in split doses. But in fact, you can give a 5 cc or 2.5 cc dose twice and neither of them cause much in the way of local problems at all. It’s very well-tolerated. In the trials, we could not tell which were fulvestrant injections and which were the placebo injections.

— Kathleen Pritchard, MD

SEQUENCE OF FULVESTRANT

The role of fulvestrant is going to be interesting, because right now this agent would be used after aromatase inhibitors, but there are studies available showing perhaps equal efficacy and, in some studies, even more efficacy than aromatase inhibitors for management of metastatic breast cancer. The different route of administration for fulvestrant is a good thing for some patients, because they won’t have to remember to take a tablet on a daily basis. On the other hand, they will have to come to the clinic once a month to receive an intramuscular injection.

— Edith Perez, MD

TRIALS 20/21: PHASE III RANDOMIZED STUDY OF ICI 182780 (FULVESTRANT) VERSUS ANASTROZOLE IN POSTMENOPAUSAL WOMEN WITH ADVANCED BREAST CANCER CLOSED PROTOCOL     A third arm in Trial 21, fulvestrant 125 mg, was closed after planned analysis demonstrated that pre-defined efficacy criteria were not met at that dose *Only the North American trial (21) had placebo controls.   TRIALS 20 AND 21: CLINICAL ENDPOINTS   Reproduced with permission from a presentation by Robert W Carlson, M.D.     TRIALS 20 AND 21: STUDY DESIGN DIFFERENCES   Reproduced with permission from a presentation by Robert W Carlson, M.D.   NCCTG-N0032: PHASE II STUDY OF FULVESTRANT (ICI 182780) IN WOMEN WITH METASTATIC BREAST CANCER WHO HAVE FAILED AROMATASE INHIBITOR THERAPY OPEN PROTOCOL O N C O LO G I S T S What first-line endocrine therapy would you recommend for the following patients with ER-positive, HER2-negative metastatic breast cancer?   TAMOXIFEN ANASTROZOLE LETROZOLE OVARIAN ABLATION NONE Asymptomatic 43-year-old woman with bone metastases who received no adjuvant therapy 60% 15% 20% 5% - Asymptomatic 63-year-old woman with bone metastases who received no adjuvant therapy 35% 30% 35% - - Asymptomatic 63-year-old woman with liver and lung metastases who received no adjuvant therapy 25% 25% 35% - 15% Very ill 63-year-old woman with liver and lung metastases who received no adjuvant therapy 15% 20% 25% - 40% Asymptomatic 78-year-old woman with bone metastases who received no adjuvant therapy 35% 30% 35% - - For how many patients have you used a second aromatase inhibitor after the patient has received a first one for metastatic disease? Median 9%

Howell A et al. Comparison of efficacy and tolerability of fulvestrant (Faslodex) with anastrozole (Arimidex) in post-menopausal women with advanced breast cancer. Breast Ca Res Treat 2000;64(1): No abstract available.

Klijn JG et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH)agonist versus LHRH agonist alone in premenopausal advanced breast cancer: A meta-analysis of four randomized trials. J Clin Oncol 2001;19:343-53. Abstract

Mouridsen H et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 2001;19(10):2596-606. Abstract

Nabholtz JM et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Results of a North American multicenter randomized trial. J Clin Oncol 2000;18(22):3758-3767. Abstract

Osborne CK. A Double-blind randomized trial comparing the efficacy and tolerability of Faslodex™ (fulvestrant) with Arimidex™ (anastrozole) in post-menopausal (PM) women with advanced breast cancer (ABC). Breast Ca Res Treat 2000;64(1): No abstract avilable.

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