Breast Cancer Research and Treatment 25: 57—63, 1993.
`© 1993 Kluwer Academic Publishers. Printed in the Netherlands.
`
`Report
`
`Toremifene and tamoxifen in advanced breast cancer — a double-blind cross-
`
`over trial
`
`Lars E. Stenbygaard,1 Jorn Herrstedt,‘ Jane F. Thomsen,2 Karsten R. Svendsen,‘ Svend Aa. Engelholm‘ and
`Per Dombernowsky1
`’ Department of Oncology, Herlev Hospital, University of Copenhagen DK-2730, Herlev, Denmark;
`2 Department of Internal Medicine C, Bispebjerg Hospital, University of Copenhagen, DK—2400 Copenhagen,
`Denmark
`
`Key words: endocrine therapy, toremifene, tamoxifen, clinical cross—resistance, advanced breast cancer,
`antiestrogens
`
`Summary
`
`Toremifene (TOR) is a triphenylethylene derivative related to tamoxifen (TAM). TOR has antitumor activ—
`ity, not dependent on estrogen receptors, and responses with TOR have been observed in patients with pro—
`gressive disease during TAM-treatment. To elucidate possible cross—resistance between these two antiestro—
`gens, we compared their anti—tumor activity in a randomized, double—blind, cross—over study.
`66 postmenopausal women with advanced estrogen receptor positive or unknown breast cancer and a
`median age of 63 years (range 38—82) were included. Patients were randomized to TAM 40mg/day or TOR
`240mg/day. Treatment continued until progressive disease, when cross-over to the alternative treatment was
`done. The response rate with first line TOR was 29% (95% confidence limits 10~41%) and with TAM 42%
`(95% confidence limits 25—61%). Response rates and response durations, survival and toxicity were not sig-
`nificantly different between the two treatments. 44 patients progressing on first line TAM or TOR were
`evaluable for second line TOR or TAM treatment. As no responses were observed, the possibility of over—
`looking a response rate of 20% or more is less than 1%.
`In conclusion, this study strongly indicates that TOR and TAM are clinically cross-resistant in patients with
`advanced breast cancer.
`
`Introduction
`
`Toremifene (TOR) is a triphenylethylene deriva-
`tive related to tamoxifen (TAM). TOR has a high
`affinity for the estrogen receptor (ER) in breast
`cancer tissue and is active against the MCF—7 breast
`cancer cell line [1]. Furthermore, TOR inhibits the
`growth of rat mammary carcinomas induced by di-
`methylbenzanthracene and causes regression of
`such tumors [2]. TOR appears to have less estrogen-
`
`ic effect than TAM at equivalent antiestrogenic
`doses [1]. In ER-negative murine uterine sarcomas,
`high doses of TOR (100 and 200mg/kg) had cyto-
`toxic activity, an effect not observed with high doses
`of TAM [2]. It has been proposed that this is inde-
`pendent of ERs and mediated by specific antiestro-
`gen binding sites [2] or by stimulation of transform—
`ing growth factor beta-1 [3].
`In phase I studies, TOR has been well tolerated in
`doses up to 460mg/day [1, 4]. In phase II trials in—
`
`Address for offprints: L.E. Stenbygaard, Department of Oncology, University of Copenhagen DK—2730, Herlev, Denmark
`
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`58
`
`LE Stenbygaard et al.
`
`eluding previously untreated patients with ER-pos-
`itive advanced breast cancer, response rates be-
`tween 48 and 68% have been observed [5—8]. These
`results are comparable to those obtained with
`TAM.
`
`Anti-tumor activity of TOR has been described
`in patients previously treated with TAM. Ebbs er a1.
`[3] treated 16 patients with locally advanced breast
`cancer who had progressed on TAM treatment with
`TOR 200 mg daily. Partial responses were observed
`in 4 patients with a median duration of 10 months
`(range 4—11). In another small study, activity of
`TOR was also observed after progression on TAM-
`treatment [9].
`The dose of TAM has been prospectively tested
`over a range of 2—100mg/m2 body surface area twice
`daily. No clear benefit of using doses higher than
`20—40mg a day was shown [10]. As a few cases of
`remission have been reported after escalating the
`daily dose of TAM from 20 to 40 mg [11], we used the
`40mg daily dose. Based on the proposed different
`mechanisms of action, when TOR is given in high
`doses compared with low doses, and on the unex—
`pected responses obtained with high-dose TOR in
`patients previously treated with TAM, we designed
`a double-blind crossover study to further elucidate
`whether TOR and TAM are clinically cross-resist—
`ant.
`
`Methods
`
`Patients
`
`Patient inclusion criteria were: histologically veri~
`fied inoperable primary, metastatic, or recurrent
`breast cancer, measurable or evaluable disease ac—
`
`[12], ER—positive
`cording to WHO criteria
`(> 10 fmol/mg protein) or unknown tumors, at least
`6 months since termination of any adjuvant endo-
`
`crine therapy, a performance status of $2 (WHO),
`and postmenopausal stage defined as: 1) more than
`one year since last menstruation or 2) surgical or
`radiation castration or 3) 255 years if a hysterecto-
`my had been performed. Patients previously treat-
`ed with TAM for advanced breast cancer or patients
`receiving corticosteroids were not eligible.
`
`Patients were randomized to TAM (40mg orally
`o.d.) or TOR (120mg orally b.i.d.). To ensure blind-
`ing of the trial, patients receiving TOR were given
`identical placebo tablets of TAM (and vice versa).
`Treatment was continued until progressive disease
`(PD) when patients were crossed over to the alter-
`native treatment.
`
`Clinical examination, tumor measurements, and
`
`thrombo—
`leukocytes,
`blood tests (hemoglobin,
`cytes,
`sodium, potassium, creatinine, calcium,
`LDH, alkaline phosphatase, bilirubin, albumin, and
`
`ASAT) were done before inclusion and then every
`4 weeks. Chest X-rays and X—ray and/or ultrasound
`of suspicious areas were performed before inclu-
`sion and then every 8 weeks or when clinically in—
`dicated.
`
`Response criteria
`
`WHO response criteria were applied [12]. Com-
`plete response (CR) was defined as disappearance
`of all evidence of disease for at least 4 weeks. In pa-
`tients with bone metastases, complete disappear-
`ance of all lesions on X-ray was required. The dura-
`tion of CR was defined as lasting from the day CR
`was firstk‘recorded until the day of PD.
`Partial response (PR) was determined by 2 ob-
`servations not less than 4 weeks apart and required
`a decrease of 50% or more in total measured tumor
`
`size; additionally, no new lesions or increase of
`225% of any lesion should be observed. In case of
`bone metastases, decrease in size of lytic lesions or
`recalcification were considered PR. The duration of
`
`PR was defined as lasting from the first day of treat-
`ment until PD. No change (NC) was only applied
`after at least 4 weeks (in case of bone metastases
`after at least 8 weeks) from start of treatment. PD
`was defined as appearance of any new lesion or an
`increase of 225% in any existing lesion.
`
`Estrogen receptor analysis
`
`Estrogen receptors were measured biochemically
`or on paraffin-embedded, formalin-fixed speci-
`mens as previously described [13, 14]. In the bio-
`
`
`
`
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`Toremifene and tamoxifen in advanced breast cancer
`
`59
`
`chemical analysis, tumors were considered ER-pos—
`itive when at least 10fmol/mg cytosol protein were
`present.
`
`Ethics
`
`The study was carried out in accordance with the
`Helsinki II Declaration and was approved by the
`Scientific Ethics Committee of Copenhagen Coun-
`ty and by The Danish Medical Health Authorities.
`
`Statistics
`
`All tests were two-tailed with a significance level of
`5%. For comparison between groups, the Mann-
`Whitney U-test was applied. For overall toxicity,
`the Chi-square test was used. Survival distributions
`were estimated by the method of Kaplan and Meier
`and compared by the log rank test [15].
`
`Results
`
`From September 1987 to March 1989, 66 patients
`were included. One patient was excluded due to ad-
`verse reactions and was evaluable for toxicity only,
`one did not have histologically verified breast can-
`cer, one received irradiation of the only evaluable
`parameter, and one had previously received TAM
`for advanced breast cancer, leaving 62 patients eva-
`luable for response to first line treatment.
`Patient characteristics are shown in Table 1. Nine
`
`patients starting treatment with TOR and 1 starting
`with TAM had liver metastases (p: 0.01). None of
`the other patient characteristics including perform-
`ance status showed any statistically significant dif-
`ference (Mann-Whitney U-test, Chi-square test).
`As of June 1992, the median observation period was
`
`19 months (range 1—56+).
`
`Responses
`
`The response rate with first line TOR was 29%
`
`Table]. Patient characteristics
`
`
`
`
` TOR (n:31) TAM (n=31)
`
`Age (years) median (range)
`
`ER positive/unknown
`Prior treatment
`None
`
`Adjuvant TAM
`Adjuvant CMF
`Adjuvant CMF+ TAM
`Chemotherapy for advanced disease
`Site of metastases
`Soft tissue
`
`Lung
`Liver
`Bone
`Number of metastatic sites
`1
`2
`23
`
`64
`(42—82)
`20/11
`
`61
`(3845)
`22/9
`
`15
`
`8
`2
`3
`3
`
`14
`
`8
`9
`15
`
`15
`11
`5
`
`.
`
`14
`
`4
`4
`3
`6
`
`18
`
`1
`13
`
`21
`7
`3
`
`Disease free interval (months)
`Median (range)
`
`33
`28
`(0454)
`(0—264)
`
`
`C : cyclophosphamide, M: methotrexate, F: 5-fluorouracil, TAM : tamoxifen, TOR 2 toremifene.
`
`
`
`
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`60
`
`LE Stenbygaard et al.
`
`Table 2. Response rate (%) in 62 patients receiving TAM or TOR
`for advanced breast cancer
`
`
`weeks after start of treatment and 4 patients died
`after more than 8 weeks of first line treatment due
`
`CR
`PR
`NC
`PD
`
`
`TOR (n: 31)
`TAM (n: 31)
`
`3
`16
`
`26
`26
`
`23
`26
`
`48
`32
`
`10 26 24Total (n : 62) 40
`
`
`
`
`
`
`
`
`
`to progressive disease. Five patients refused to com—
`plete the cross-over. Two patients are still being
`treated in the first period, leaving 44 patients who
`have completed the cross-over and are evaluable
`for response to second line treatment. Of these pa-
`tients, 21 initially received TOR and crossed over to
`TAM and 23 initially received TAM and crossed to
`TOR. Patient characteristics are given in Table 3.
`
`Prognostic factors did not differ significantly be—
`tween the two groups. Seventeen patients receiving
`TOR after the cross-over (74%) and 11 receiving
`TAM (52%) were ER-positive (p : 0.24, Chi-square
`test) and three patients in each group had liver me-
`tastases. Seven of the 44 patients died due to PD
`within 8 weeks after the cross-over. No responses
`were observed (Table 4) in the 37 patients who com—
`pleted at least 8 weeks treatment after the cross-
`
`over. Twelve patients (27%) had NC with a median
`duration of 6 months (range 2—28(+)); 7 of these pa-
`tients received TOR, 5 received TAM.
`
`TAM: tamoxifen, TOR: toremifene.
`
`(95% confidence limits 10—41%) and with TAM
`42% (95% confidence limits 25—61%). The median
`duration of CR was 18 months (range 4—56+) and
`for PR 11 months (range 3—26). The combined re—
`sponse rates are shown in Table 2. Five patients are
`still on-study. Two patients treated with TAM as
`first line treatment continue in CR after 46+ and
`
`56+ months, respectively. Three patients with PD
`after first line treatment continue in NC after cross—
`
`over to second line treatment, with the following
`durations of NC: TAM: 24+, 28+ and TOR: 28+
`months.
`
`Of the 62 evaluable patients, 7 died within 8
`
`Figure 1 shows survival curves for patients initial-
`
`Table 3. Patient characteristics among 44 patients after cross-over from TOR to TAM (or vice versa)
`Treatment after cross-over
`
`
`
`
` TOR (n: 23) TAM (n: 21)
`
`Age (years) median (range)
`
`ER positive/unknown
`Prior treatment
`
`Adjuvant TAM
`Adj uvant CMF
`Adjuvant CMF+ TAM
`Chemotherapy for advanced disease
`TAM or TOR as the only previous treatment for advanced disease
`Site of metastases
`Soft tissue
`
`59
`(38—75)
`17/6
`
`4
`4
`2
`5
`9
`
`17
`
`66
`(43—82)
`11/10
`
`3
`1
`1
`1
`14
`
`11
`
`Lung
`Liver
`Bone
`Number of metastatic sites
`1
`2
`23
`Disease free interval (months)
`28
`34
`Median (range)
`
`(0—154) (0—180)
`
`9
`3
`13
`
`9
`7
`5
`
`11
`3
`11
`
`11
`7
`5
`
`C: cyclophosphamide, M : methotrexate, F : S-fluorouracil, TAM: tamoxifen, TOR: toremifene.
`
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`Toremifene and tamoxzfen in advanced breast cancer
`
`61
`
`ly treated with TAM and TOR, respectively. There
`was no significant difference between the two treat-
`
`ment groups (p: 0.16).
`
`Toxicity
`
`Adverse reactions were few and generally mild.
`One patient receiving TOR was excluded due to
`nausea, vomiting, and headache. Overall, 8 patients
`treated with TOR and 5 with TAM as first line treat-
`
`ment reported one or more adverse reactions con—
`sisting of mild to moderate flushing, headache, or
`nausea. The toxicity was most pronounced during
`the first months of treatment. None of the patients
`reported adverse reactions when receiving TAM or
`TOR as second line treatment.
`
`Discussion
`
`This study was designed to investigate possible non-
`cross resistance between TAM and TOR in patients
`with advanced breast cancer. The combined re—
`
`sponse rate with first line TOR or TAM was 36%
`(95% confidence limits 21—46%) and is comparable
`to other studies with antiestrogens [5,16]. However,
`due to the limited number of patients included, the
`study was not designed to compare TOR and TAM
`as first line endocrine treatment for metastatic dis—
`ease.
`
`When this study was planned, no blinded com-
`parative phase III trials with these two antiestro—
`gens had been initiated, and the previously report-
`ed response rates were therefore based on open
`trials [17]. In our blinded cross-over trial, no re—
`sponses were observed among 21 patients crossing
`
`Table 4. Response rate (%) in 44 patients receiving TOR or TAM
`as second line endocrine treatment for advanced breast cancer
`
`
`CR
`PR
`NC
`PD
`
`
`TOR (n = 23)
`TAM (n: 21)
`
`0
`0
`
`0
`0
`
`30
`24
`
`70
`76
`
`0 0 27Total (n = 44) 73
`
`
`
`
`
`
`
`
`
`TAM = tamoxifen, TOR : toremifene.
`
`Probability of survival
`1
`
`0.6
`
`0,8
`
`
`0.4
`
`0.2
`
`p=0.16, log‘rank test
`
`0
`
`200
`
`400
`
`600
`
`800
`
`1000
`
`1200
`
`1400
`
`1600 Days
`
`Fig. 1. Survival curves (Kaplan-Meier plot) for 31 patients treat-
`ed with TAM and 31 patients treated with TOR as first line en-
`docrine therapy for advanced breast cancer (p: 0.16).
`
`from TOR to TAM, or among 23 crossing from
`TAM to TOR. This means that the possibility is less
`than 1% for overlooking a response rate of >20%
`with TAM or TOR as second line endocrine treat-
`
`ment for metastatic disease [18]. The fact that no
`responses were observed after cross-over from
`either of the two first line antiestrogens strongly in—
`dicates clinical cross—resistance between TOR and
`TAM.
`
`Among the 22 patients who responded to TOR or
`TAM as first line endocrine treatment for advanced
`
`disease, 15 crossed over to the alternative treatment
`
`after PD. In this selected group, no responses were
`observed with second line treatment, as 8 patients
`had NC and 7 PD. Our study was initiated based on
`the proposed different mechanism of action of
`TOR [2] and the promising results from the study
`by Ebbs et al. [3]. Other studies have also demon—
`strated a low response rate with TOR, ranging from
`0—7 %, in patients who 1) did not respond to tamoxi—
`fen treatment, or 2) had progressive disease after
`initial response on TAM, or 3) had progressive dis—
`ease during adjuvant TAM [15,19—22]. On the other
`hand, response to TAM has been reported after re-
`treatment with TAM following an observation peri-
`od without treatment [23]. This phenomenon could
`explain the few responses reported with TOR after
`PD following TAM treatment.
`The (non—significant) difference in the survival
`curves after first line treatment with TOR and TAM
`
`is probably due to the fact that 9 of 10 patients with
`liver metastases, whom of which 5 died within a few
`weeks and 16 of 26 with 2 or more metastatic sites
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`62
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`LE Stenbygaard et a].
`
`(Table 1) were randomized to first line TOR treat—
`ment. Furthermore, more TOR—treated patients
`
`had been exposed to adjuvant TAM (11 vs. 7 pa-
`tients). In patients with advanced breast cancer and
`progression on TAM-treatment, response rates of
`5—10% have been obtained with megestrol acetate
`or aminoglutethimide [24, 25]. In patients with pre-
`vious response to TAM the response rate is from 30
`to 40% [24]. For second line treatment, therefore, it
`seems reasonable to recommend one of these other
`
`endocrine therapies [25].
`In conclusion, this study was not designed to in-
`vestigate differences in response rates of TAM and
`TOR as first line endocrine treatment for advanced
`
`disease, but rather to examine the potential clinical
`non-cross—resistance between TAM and TOR. Our
`
`cross-over data strongly indicate clinical cross-re-
`sistance between the two drugs. Second-line treat-
`ment with TOR after treatment with TAM (or vice
`versa) in patients with advanced breast cancer is
`thus not meaningful.
`
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