SOUTHAMPTON PRINCESS, BermudaThree large randomized studies comparing the antiestrogens toremifene (Fareston) and tamoxifen (Nolvadex) in patients with advanced breast cancer showed no significant differences in efficacy or toxicity, Richard A. Gams, MD, of the James Cancer Hospital, Ohio State University, said at a symposium on antiestrogen therapy for breast cancer sponsored by Schering.
Although the primary use of toremifene will eventually be in the adjuvant and chemoprevention settings, Dr. Gams said, it was our opinion, and that of the FDA, that we first had to show efficacy in advanced disease before we could move on to adjuvant trials.
Toremifene differs from tamoxifen in its chemical structure by a single substitution of a chlorine atom, a difference that affects the drugs interaction with DNA. Preclinical studies suggest that toremifene may be less likely than tamoxifen to lead to the formation of DNA adducts, which may be responsible for the development of the secondary malignancies sometimes seen with long-term adjuvant tamoxifen use.
This is one of the major concerns for women taking this drug for a long period of time, and could potentially be obviated with use of toremifene, he said.
Because of the difficulty of finding sufficient numbers of tamoxifen-naïve patients in the United States, the initial US trial was expanded to Canada and Mexico (and eventually to South Africa, the United Kingdom, Australia, and New Zealand) and became known as the North American trial. A second trial in the then-Soviet Union, which included some of the Baltic countries, became known as the Eastern European trial. The third study, known as the Nordic trial, included patients primarily from Finland, Sweden, Norway, and Denmark, but also several Eastern bloc countries.
Trials Similar in Design
These three trials were coordinated to be as similar as possible in design, each using a toremifene dose of 60 mg/day. The North American trial used a 20 mg/day tamoxifen dose for comparison, and also tested a high-dose toremifene arm (200 mg).
The Eastern European trial also included a high-dose toremifene arm (240 mg), and used a tamoxifen dose of 40 mg, which was the common dose used in Europe at the time. The Nordic trial used the same 40 mg tamoxifen dose and did not have a high-dose toremifene arm.
In the North American trial, patients were peri- or postmenopausal, whereas in the other trials all patients were postmenopausal. Patients were ER or PR positive or status unknown. If they had received adjuvant tamoxifen previously, they must have been off tamoxifen for at least 12 months. Vasomotor side effects with initial therapy were similar for both drugs, Dr. Gams said, so it is unlikely that toremifene could be used in patients intolerant of tamoxifen.
Two cases of endometrial carcinoma were seen, both in women on the tamoxifen arm. To my knowledge, Dr. Gams said, there is yet to be a case of endometrial carcinoma in women treated with toremifene. And there have now been a considerable number of women-years of therapy with this antiestrogen.
The response rates for toremifene 60 mg and tamoxifen, 20 mg or 40 mg, were virtually identical in both the North American and Eastern European trials, although lower than anticipated. We saw 20% response rates, Dr. Gams said, whereas we anticipated 40% to 50% response rates.
The explanation, he believes, lies in the trials stringent protocol for disease measurement. We insisted that all disease be measured, not just single tumors, he said. Secondly, the response had to last for two examination periods (8 weeks since CT and MRI were being done every eight weeks). All responses were independently reviewed by several different blinded reviewers, and frequently responses were downgraded to stable disease because they did not quite meet the stringent criteria.
Finally, Dr. Gams pointed out, the trials included a large number of patients with bone-only disease. We could show disease stability in these patients, but objective responses are rare in these patients with dominant bone disease.
In terms of response, the Nordic trial was a bit of an outlier, he said, in that response rates were somewhat higher, 30% to 37%.
Time to Progression
In both the North American trial and the Eastern European trial, time to progression was identical. The disappointment, of course, is that the median time to progression is only about six months, Dr. Gams said.
There was no difference in event-free or overall survival in any of the trials. And although antiestrogens do not significantly prolong survival in advanced disease, they do appear to have favorable effects on quality of life. In the North American trial, he said, about half of the patients had improvement in performance status while on antiestrogens, due primarily to improved pain scores.
In the North American and Eastern European trials, he said, the higher dose of toremifene produced slightly better response rates than tamoxifen, suggesting that there may be a role for second-line high-dose toremifene in patients who have failed standard doses. The agent is approved for this use in Japan.
Dr. Gams reiterated that these trials were only the first step in toremifene research. Their purpose was to show equivalent safety and efficacy so that we could feel comfortable launching the trials that really counttrials in the adjuvant and chemoprevention settings.