Trial of Toremifene vs Tamoxifen as Adjuvant Breast Cancer Therapy

SOUTHAMPTON, Bermuda—Shortly after the publication of trial results showing similar efficacy of antiestrogens toremifene (Fareston) and tamoxifen (Nolvadex) in metastatic breast cancer, the Finnish Breast Cancer Group started to plan a comparison study of the two agents as adjuvant breast cancer therapy, said Kaija Holli, MD, of Tampere University Central Hospital, Tampere, Finland.

The randomized study of tamoxifen, 20 mg/day, vs toremifene, 40 mg/day, for 3 years in postmenopausal women with node-positive disease began in 1992. Tamoxifen for 3 years is the standard treatment approach for these patients in Finland, Dr. Holli said at a symposium on antiestrogen therapy in breast cancer, sponsored by Schering-Plough, manufacturer of toremifene.

Patients in the study must be no more than 10 weeks from surgery and have good performance status. “We are not taking patients with inflammatory carcinomas or those with metastatic disease, previous cancers, or previous thrombo-embolic disease,” she said.

The endpoints are time to first relapse, disease-free survival, relative survival, and death from causes other than breast cancer, and the researchers are closely monitoring for adverse events, she said. Patients are followed every 3 months initially, then every 6 months up to the end of the treatment, then once a year.

“We’re asking about symptoms and recording possible side effects. We take the patient’s weight, do laboratory tests, including liver enzymes, and do chest x-ray and other diagnostic examinations if needed,” Dr. Holli said.

Finland, with a population of only 5.3 million, has five major University hospitals, each with its own cancer clinic, as well as several central hospitals that also have cancer treatment facilities. This trial is the first to involve all nine centers in Finland that treat primary breast cancer, Dr. Holli said. She noted that breast cancer is the most common cancer in Finland, with about 3,000 cases annually.

Since Finland has a free population-based mammography screening program for women between the ages of 50 and 65, most breast cancers picked up in that age group are early-stage node-negative disease; 30% of the patients in the trial are age 70 or older.

Interim Analysis

The researchers have enrolled 960 patients to date, with a target goal of 1,460. An interim analysis when enrollment reached 500 showed no problems with randomization, ie, no differences in patient or tumor characteristics between the two treatment groups; no difference in relapse rates; and no significant difference in serious side effects, Dr. Holli said.

Dr. Holli reported on a preliminary analysis of serious side effects in 900 patients enrolled to date. There have been 6 cases of myocardial ischemia, 8 vascular disorders, 16 cases of thromboembolism, and 8 endometrial disorders, such as bleeding, but no endometrial cancers. No significant differences between the two groups have been seen, although there is a trend toward more thromboembolic events in the tamoxifen group.

She acknowledged in the question and answer session after her talk that, in fact, the study may not be large enough to show significant differences in the incidence of serious but rare side effects such as endometrial cancer.

Dr. Holli mentioned that other randomized controlled trials of toremifene versus tamoxifen as adjuvant treatment of breast cancer are being conducted in Europe. These trials, she said, are employing a more complicated design that includes chemotherapy and randomizes patients to four different treatment arms in one trial and six arms in another. These trials are also using a higher, 60-mg toremifene dose, and are continuing both agents for 5 years instead of 3 years as in the Finnish trial.

“Although they are quite different studies,” she said, “they are looking at the same aspects.”