Adjuvant Trials of Toremifene vs Tamoxifen: The European Experience

ABSTRACT: When results from the phase II trials of toremifene (Fareston) and tamoxifen (Nolvadex) in metastatic breast cancer were published, the Finnish Breast Cancer Group began to plan the first trial of toremifene in an adjuvant setting. This multicenter, randomized trial is comparing toremifene (40 mg/d) to tamoxifen (20 mg/d) in postmenopausal lymph node-positive breast cancer patients. Treatment duration is 3 years. About 1,150 of a planned 1,460 patients have been enrolled to date. The International Breast Cancer Study Group is also conducting two adjuvant trials evaluating 5 years of toremifene (60 mg/d) vs tamoxifen (20 mg/d). More than 1,000 patients have been enrolled in these studies to date. The efficacy of toremifene is being explored in all of these trials. In the Finnish trial, additional protocols are evaluating treatment side effects, including the formation of DNA adducts in the endometrium and leukocytes, certain ocular problems, thromboembolic events, and subjective side effects. The effects of toremifene on lipid levels and bone density are also being studied. An interim safety analysis, performed in the Finnish study after 500 patients were enrolled (mean follow-up, 18 months), showed no significant differences between toremifene and tamoxifen in terms of efficacy or side effects. Toremifene seems to be well tolerated and may have additional positive effects. Ongoing trials will soon reveal how beneficial toremifene is in the adjuvant setting and whether it is devoid of the adverse effects observed with tamoxifen.[ONCOLOGY(Suppl 5):23-28, 1998]

Meta-analysis has demonstrated a significant benefit of adjuvant antiestrogens on both recurrence rates and mortality from breast cancer in postmenopausal women.[1] The adverse effects of tamoxifen (Nolvadex) have been widely discussed recently. The main concern is the increased number of endometrial cancers in tamoxifen-treated patients.[2-4] On the other hand, there is a significant decrease in cancers of the contralateral breast in tamoxifen-treated patients compared to controls.[5]

Toremifene (Fareston), a newer antiestrogen synthesized in 1981 in Finland, has been studied in animal experiments and clinical trials in metastatic breast cancer.[6-9] When the results of the first phase II studies of toremifene and tamoxifen in metastatic breast cancer were published in the early 1990s, the Finnish Breast Cancer Group started to plan the first adjuvant trial of toremifene. Shortly thereafter, the International Breast Cancer Study Group also began planning adjuvant trials of toremifene.

This article will summarize the randomized, multicenter, adjuvant trials currently in progress in Europe that are comparing toremifene and tamoxifen. The study design of all of these trials and very preliminary safety results of the Finnish trial will be discussed.

Trial Designs

Finnish Trial

The Finnish multicenter adjuvant trial began in 1992. It was first started in four University Cancer Clinics but was later extended to all nine cancer clinics in Finland. The study is being conducted by the Finnish Breast Cancer Group, an independent scientific group. The trial is a randomized comparison of tamoxifen (20 mg/d) vs toremifene (40 mg/d) as adjuvant therapy for postmenopausal, lymph node-positive breast cancer patients in Finland (Figure 1). The duration of treatment is 3 years, and both the efficacy and side effects of the therapies are being explored.

Inclusion and exclusion criteria for the study are listed in Table 1. The main end points are recurrence rate, disease-free survival, and overall survival. Other potential positive effects of the treatments are also being studied, along with subjective side effects and other adverse events. Additional protocols are listed in Table 2.

One additional protocol is studying the effect of toremifene and tamoxifen on the endometrium during adjuvant treatment by measuring the formation of DNA adducts in the endometrium. About 100 patients will be enrolled in this protocol. In addition, in order to monitor patients for possible endometrial changes during treatment, every patient in the main protocol who is not hysterectomized is undergoing an ultrasound and endometrial biopsy upon entry and after 2 years of treatment.

At trial entry and at specific intervals during and after therapy, patients are being followed for adverse effects and undergo various clinical tests. Follow-up is scheduled every 3 months for the first 6 months of therapy and then every 6 months until treatment is stopped. Thereafter, patients are monitored annually for 10 years (Table 3). Subjective side effects are elicited from patients by questionnaire, and a physician interviews patients concerning any symptoms and side effects that they may be experiencing.

Randomization is being performed centrally by the Finnish Cancer Registry, where the data are also being analyzed. At the beginning of 1997, the Finnish Breast Cancer Group decided to monitor the study. The study also has a follow-up group consisting of three people not involved in the trial (statistician, epidemiologist, and oncologist) who receive annual reports of relapse rates and any serious side effects to confirm the safety of the study.

International Breast Cancer Study Group Trials

The International Breast Cancer Study Group is coordinating two trials comparing toremifene to tamoxifen. Trial 12 has a target population of 1,140 postmenopausal and perimenopausal patients with lymph node-positive disease. Patients are being randomized to receive one of three regimens: (1) four cycles of AC (Adriamycin and cyclophosphamide) plus concurrent and subsequent tamoxifen or toremifene; (2) four cycles of AC plus subsequent tamoxifen or toremifene; or (3) tamoxifen or toremifene alone. The tamoxifen dose for this trial is 20 mg/d and the toremifene dose is 60 mg/d. The duration of treatment is 5 years.

Trial 14 has a target population of 840 postmenopausal and perimenopausal patients with lymph node-positive breast cancer. All patients will receive chemotherapy. Patients are being randomized to receive either: (1) four cycles of AC, followed by four cycles of CMF (cyclophosphamide, methotrexate, and fluorouracil), and then by tamoxifen or toremifene; or (2) four cycles of AC, followed, after a 16 week treatment-free gap, by three cycles of CMF, and then by tamoxifen or toremifene. Endocrine treatment duration is 5 years, and doses are 20 mg/d of tamoxifen and 60 mg/d of toremifene.[10]

Methodology of the Finnish Trial

To date, about 1,100 patients have been enrolled in the Finnish study. The recruitment rates are proceeding as had been expected (Figure 2). In the power calculation, it is assumed that the disease-free survival rates (estimated to be 65%) are equal for the two agents with the analyses performed when about 35% of patients have recurrent disease. If the equivalence limit for the hazard ratio (toremifene vs tamoxifen is set to 0.80 (LOGO.65/LOGO.58), a total of 1,460 evaluable patients (730 per group) are required (two-sided alpha = .05; power = ,80).[11]

Interim Safety Analysis

An interim analysis, done mainly for safety purposes, was performed after the first 500 patients were enrolled. The randomization was successful, with patients divided equally between the two groups (246 in group 1 and 254 in group 2). No differences were seen between the treatment groups with respect to patient and disease characteristics, including patient age, tumor size, hormone receptor status, and number of positive lymph nodes (Table 4).

After a mean follow-up of 18 months, no significant differences were noted between the treatment groups with regard to relapse rates (10% vs 11%) or the incidence of serious adverse events. The most common adverse events were deep-vein thrombosis, pulmonary embolism, myocardial infarction, and cerebrovascular disorders (Table 5). The most common subjective side effects were hot flashes and sweating. Three patients stopped treatment due to subjective side effects.

Discussion

Tamoxifen has been an effective endocrine therapy for metastatic breast cancer, as well as in the adjuvant setting. It is now also being tested in chemoprevention trials.[12] Tamoxifen is a well tolerated treatment with benefits that far outweigh its risks. In addition to its ability to prevent recurrences and contralateral breast cancers, tamoxifen has a favorable effect on bone density and serum lipid levels.[13-15] However, recent studies have found an increased incidence of endometrial cancers in tamoxifen-treated patients, compared with controls.[16]

Toremifene has been shown to be as effective an antiestrogen as tamoxifen in metastatic disease.[17] It is thought to have similar efficacy as an adjuvant therapy for breast cancer, and three ongoing trials are currently studying toremifene in this setting.

It has been theorized that toremifene may not have the same kind of adverse effects as tamoxifen. However, there are insufficient data supporting the long-term use of toremifene to date. One hypothesis that may explain why tamoxifen has been associated with an elevated frequency of endometrial cancer is a possible direct genotoxic and carcinogenic effect secondary to increased DNA modification—an effect that has not been observed with toremifene. Animal studies support this fact.[18,19] However, endometrial changes may also be due to the partial estrogenic effect of the antiestrogens.

More long-term data on toremifene are needed before any firm conclusions can be made about its possible side effects and potential positive effects besides prevention of breast cancer recurrence. The ongoing Finnish adjuvant study will answer many open questions. If trial enrollment continues at the same pace as it has up to now, results may be available within 2 years. Results of some of the additional protocols, such as those focusing on serum lipid levels and DNA adducts of leukocytes, may be ready sooner.

In a recent study by Saarto et al, toremifene was observed to increase serum high-density lipoprotein (HDL) levels to a greater extent than did tamoxifen. This study thus provides evidence that toremifene has antiatherogenic properties, with the potency to improve all lipoproteins associated with increased coronary heart risk.[20] However, the number of cases in this study was small.

In the Finnish adjuvant study, lipid levels are being monitored at entry, during follow-up, and after treatment. Control breast cancer patients, who do not receive any antiestrogens, are also included in this study.

Two other ongoing European trials are also comparing toremifene to tamoxifen in the adjuvant setting. These studies, which are being coordinated by the International Breast Cancer Study Group, differ from the Finnish study with regard to both dosage and duration of endocrine treatment. In the International Breast Cancer Study Group studies, toremifene is being given at a dose of 60 mg/d and tamoxifen at 20 mg/d. Both endocrine agents are being administered either alone or in combination with chemotherapy. The duration of treatment is 5 years.

More than 1,000 patients have been enrolled in these trials to date, and it is likely that the results will be available at about the same time as those of the Finnish study. Both trials will yield important information on the long-term use of toremifene at a higher dose than is being employed in the Finnish study.

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