Toremifene(Drug information on toremifene) (Fareston) is the first antiestrogen introduced into US clinical oncologic practice since tamoxifen(Drug information on tamoxifen) (Nolvadex) was approved for use in postmenopausal breast cancer patients approximately 2 decades ago.
Phase I clinical trials of toremifene administered orally at doses ranging from 10 to 400 mg/d[1-4] established the drugs excellent tolerability in cancer patients at virtually all dose levels, with a subjective toxicity profile similar to that of tamoxifen. Nausea and vertigo were noted in two of five healthy postmenopausal volunteers who received a dose of 680 mg/d.
Three responses were seen in the phase I trial reported by Hamm et al. All three responders were treated with a dose of 200 mg/d, and two had previously responded to tamoxifen but had subsequently progressed.
Postmenopausal Women With Positive or Unknown ER Status
Six trials of toremifene were performed in postmenopausal women with metastatic breast cancer and positive or unknown estrogen-receptor (ER) status. In two trials, which tested a dose of 20 mg/d, response rates in a total of 104 patients were 21.4% and 22.2% in ER-positive and ER-unknown women.
Four trials administered 60 mg/d to a total of 195 women. Response rates in these women ranged from 32.6% to 54.3%, with median times to progression of 6.3 to 12.2 months.
Only one published trial has used an intermediate dose of 40 mg/d. This trial reported a response rate of 33.4% in 81 patients and a median time to progression of 5.5 months. This latter result was similar to the 32.6% response rate and 6.3-month time to progression seen with the 60-mg/d dose in the same trial.
In their recent update of a previously unpublished but reviewed trial,[2,6] Hietanen and co-workers treated 73 women with 240 mg/d of toremifene and achieved a 59% objective response rate among the 56 patients evaluable for response (47% overall response rate). Although difficult to discern from the latter publication, the 15.2-month time to progression listed for this study by Hamm et al is impressive. In addition, Hietanen et al reported that six patients responded for 2 to 4 years and four additional patients responded for 5 to 7 years.
Commentary on These DataAlthough inconclusive, these phase II data suggested that a toremifene dose of 20 mg/d may be suboptimal, and led to the recommendation of the 60-mg/d dose for the subsequent phase III trials. It remains unclear whether a dose of 40 mg/d is equivalent or inferior to 60 mg/d, but that issue is unlikely to be of major clinical import.
The time to progression of 15.2 months achieved with the high dose of toremifene in the study by Hietenan et al is tantalizing, especially given the number of responses lasting for 2 to 7 years. In contrast, however, pooled data from two phase III trials involving 369 patients did not seem to show any significant benefit of high doses of toremifene compared with standard doses of tamoxifen and toremifene.
The use of high-dose toremifene in women with receptor-negative tumors is based on a report of the activity of high-dose toremifene in an estrogen-independent uterine sarcoma model and on speculations by Ebbs and co-workers that antiestrogens may produce antitumor effects distinct from those mediated by estrogen receptors. No antitumor responses were seen in one study by Perry et al of 400 mg/d of toremifene in 20 patients nor in a second study of 15 additional patients cited by Valavaara. Valavaara noted that 4 of 15 patients in the latter unpublished study had minor responses or disease stabilization for more than 6 months.
Patients Refractory to Tamoxifen
All five published trials of toremifene conducted in patients who had been previously treated with tamoxifen used doses higher than the standard 60-mg/d dose recommended for first-line therapy (Table 1). The trials of Modig et al, Ebbs et al, and Vogel et al used a dose of 200 mg/d, while Pyrhonen et al used 240 mg/d and Asaishi et al used 120 mg/d. In the European experience with toremifene as second-line therapy, as summarized by Kangas for publication in a review by Hamm, an additional 356 patients previously exposed to tamoxifen were treated with 240 mg/d of toremifene.
Commentary on These DataWhile most of the response rates reported in these trials were consistent (and low), the interesting but, at first glance, puzzling observations of Kangas, warrant comment. Patients previously treated with tamoxifen alone had a low (8%) response rate to toremifene, consistent with other series. However, the response rate to toremifene in patients pretreated with both chemotherapy and tamoxifen was higher16%. Although the lack of publication makes analysis of the actual data impossible at present, it could be that patients who did not respond to tamoxifen were subsequently treated with chemotherapy, and toremifene was administered after this intervening therapy. Responses to tamoxifen rechallenge after initial tamoxifen failure and then intervening therapies can occur, and have been seen by this author, although the reports are largely anecdotal. It is possible that the higher response rate of 16% in this subset of patients reported by Kangas could share the same mechanism of incomplete antiestrogen resistance encountered in some patients rechallenged with tamoxifen after intervening therapies.
Another factor confounding the evaluation of the seemingly consistent negative results of these phase II trials of tamoxifen-pretreated patients is the assessment of prolonged stable disease. For some time, Robertson et al and Howell et al have suggested that prolonged stable disease for more than 6 months should be considered a surrogate for antitumor response. More recently, in a randomized trial of anastrozole(Drug information on anastrozole) (Arimidex) vs megestrol(Drug information on megestrol) acetate, the 2-year survival rates of patients who had an objective antitumor response and those who had prolonged stable disease as their best response were virtually identical with either drug. These data would appear to be supportive of therapeutic clinical benefit in at least some cases of prolonged stabilization, in contrast to the usual explanation of indolent progression without clinical benefit.
The only phase II trial of toremifene in tamoxifen-resistant patients that specifically reported on a population of patients with stable disease for more than 6 months was that by Asaishi et al. These researchers concluded that an overall objective response rate of 12% plus a 15% rate of stable disease for more than 6 months equated to a 27% rate of clinical benefit. These data were sufficient to permit the registration of toremifene (at a dose of 120 mg/d) in Japan for use in patients who do not respond to tamoxifen.
In the series by Vogel et al, no reappraisal of the 23% of patients whose best response was stable disease has yet been performed to define the subset of patients with stable disease for more than 6 months. It remains possible that the overall clinical benefit rate in that previously reported negative trial could be similar to the rate seen in the trial from Japan.
With such conflicting data from phase II trials, it is impossible to determine whether or not doses of toremifene in excess of 60 mg/d could produce clinical benefit in patients who previously did not respond to tamoxifen therapy. The prolonged disease stabilization observed in some receptor-negative women cited by Valavaara and in patients refractory to tamoxifen cited by Asaishi et al raises questions about the possible clinical benefit of moderate- to high-dose toremifene in those patient subsets. If such an effect does exist, it is unlikely to be greater than 20% to 30%. Moreover, whether the same result could be achieved by tamoxifen rechallenge remains speculative.
Favoring the antiestrogen rechallenge hypothesis, as opposed to a toremifene dose-response effect, is a publication by Gershanovich et al, which summarizes the results of high-dose toremifene vs tamoxifen in two large-scale, randomized, phase III trials. In that analysis, standard-dose tamoxifen and high-dose toremifene appeared to be statistically equivalent with respect to disease progression and survival. Additional randomized clinical trials of toremifene may well be warranted in tamoxifen-refractory patients, especially in those who received several other therapeutic interventions after relapsing on tamoxifen. In such trials, toremifene could be compared to tamoxifen rechallenge.