Acm Ont'ulogira Vol. 3l. N0. 4, pp. 4257428, I992
`
`DROLOXIFENE—A NEW ANTI-ESTROGEN
`
`A phase II study in advanced breast cancer
`
`HELGE HAARSTAD, STEIN GUNDERSEN, ERIK WlST, NILS RAABE, OLAV MELLA and STENER KVINNSLAND
`
`Twenty-six patients with advanced breast cancer were treated with a new anti-estrogen, Droloxifene
`(3-hydroxy-tamoxifen). They had all used tamoxifen either in the adjuvant or the advanced situation.
`The dose schedule was 100 mg orally daily. Partial remissions were observed in 4 ( 15%) of the patients,
`and in another 5 patients stable disease ( > 24 weeks of duration) was observed. Three of the responders
`were resistant to tamoxifen. Fourteen of the 26 patients had no side-effect. In 2 patients therapy had
`to be stopped due to fatigue. Droloxifene seems to be an interesting new anti-estrogen which should be
`further exploited.
`
`Endocrine therapy is the most important systemic ther-
`apy in breast cancer in both adjuvant (l, 2) and advanced
`situations (2). Due to its documented effects and favorable
`side—effect profile, the anti-estrogen tamoxifen is the pre-
`vailing first-line choice among the endocrine treatment
`alternatives (2, 3). To further improve endocrine therapy,
`it will above all be necessary to select drugs and schedules
`resulting in higher efficacy (higher
`response rates and
`prolonged duration of effects) and/or a more favorable
`side—effect profile (4).
`New anti—estrogens as Toremifene (chlor-tamoxifen) and
`Droloxifene (3-hydroxy-tamoxifen) have recently been in-
`troduced in clinical
`trials, after promising results from
`preclinical testing (5, 6). Droloxifene has a shorter half-life
`in animals (7) and humans (8. 9), and has been claimed to
`be less estrogenic than tamoxifen in animals and in in vitro
`experiments (10). Some dose dependent estrogenicity has
`also been shown in humans (9).
`
`
`Submitted 10 July [991.
`Accepted [3 November I991.
`Correspondence to: Professor Stener Kvinnsland, Dept. of Oncol-
`ogy. The Norwegian Radium Hospital. Montebello, N-03l0 Oslo
`3, Norway.
`Addresses: Dept. of Oncology: University Hospital of Trondheim.
`Trondheim (H. Haarstad), University Hospital of Tromso,
`Tromso (E. Wist), Ulleval Hospital, Oslo (N. Raabe), Haukeland
`Hospital. Bergen (O. Mella) The Norwegian Radium Hospital.
`Oslo (S. Gundersen, S. Kvinnsland).
`
`Based on these promising preclinical data, the Norwe-
`gian Breast Cancer Group (NBCG) decided to start a
`phase II trial with Droloxifene in advanced breast cancer,
`as second- or third-line endocrine treatment.
`
`Material and Methods
`
`Twenty-five postmenopausal women and one man with
`metastatic breast cancer were included in this study. Pa-
`tient characteristics are given in Table 1. Patient inclusion
`criteria were:
`I)
`recurrent, evaluable disease; 2) post-
`menopausal (or male); 3) Steroid receptor in primary
`tumor and/or metastasis positive (>10 pmoI/g) or un-
`known; 4) previous tamoxifen treatment
`in adjuvant or
`metastatic situation (stopped >3 months before Drolox—
`ifene treatment); 5) all other anti-cancer treatment stopped
`at least 3 weeks before start of Droloxifene; 6) perfor-
`mance status >4 (11); and 7) life expectancy of more than
`3 months.
`
`The aim of the study was, within this rather heteroge—
`neous group of patients,
`to evaluate preliminarily the
`eflicacy (response rate and duration) and safety of the
`drug. The number of patients to be included was 25—30.
`with a stop after the first 14, if no responses had been seen.
`The dose was Droloxifene l00 mg orally once daily. Tu-
`mor response was evaluated according to the UICC stan-
`dards (11). The study was approved by the regional ethical
`commitee.
`
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`426
`
`H. HAARSTAD ET AL.
`
`Table 1
`
`Patient pretreatment characteristics
`
`No. of cases
`
`Total No. of patients
`Age at diagnosis. median (range)
`DFI, median (range) (n = 26)
`Previous therapy
`Endocrine therapy
`Tamoxifen
`
`Ooophorectomy
`
`Progestins
`MPA
`MA
`Both (in sequence)
`AG
`
`Other
`
`Chemotherapy
`
`Time from first rec. until
`start of Droloxifene, median (range)
`Main metastatic location
`
`No. of metastatic locations
`
`57 (32779) years
`44 (0—165) months
`
`Adjuvant
`Metastatic disease
`Both
`
`Adjuvant
`Metastatic disease
`
`Metastatic disease
`Metastatic disease
`Metastatic disease
`
`Metastatic disease
`
`Metastatic disease
`
`Doxorubicin, weekly
`FuMi
`Other
`
`24(1—87) months
`
`Soft tissue
`Bone
`Viscera
`Liver
`Lung
`Both
`
`1 location
`2 locations
`>2 locations
`
`26
`
`6
`2]
`1
`
`2
`3
`
`8
`12
`2
`
`4
`
`l
`
`5
`3
`1
`
`ll
`7
`8
`3
`4
`1
`
`l7
`7
`2
`
`DFI = disease-free interval; MPA = medroxyprogesterone acetate (500 mg x 2
`orally); MA = megestrol acetate (160 mg x 1); AG = aminoglutethimide (250 mg
`x 4 with hydrocortisone); Weekly doxorubicin, 20 mg weekly (fixed dose);
`FuMi = 5-fiuorouracil (l 000 mg/mz, day I and 2) and mitomycin C (6 mg/mz.
`day 2) q 3 weeks.
`
`Results
`
`As seen from Table l, the patients had been treated with
`at least one endocrine modality before start of Droloxifene.
`
`In 21 patients more than one endocrine and/or chemoter-
`apeutic modality (results not shown) had been used.
`An objective remission was observed in 4 patients
`(Table 2). No complete remission was seen. Three of the
`four objective responders had progressed on tamoxifen,
`two after initial response in the advanced situation, and
`one while on adjuvant tamoxifen. The last of the respon-
`ders had stopped adjuvant tamoxifen more than 1 year
`before start of Droloxifene. In another 5 patients a stabi-
`
`lization was observed, SD = 24 weeks, i.e. in 9/26 a mean-
`ingful response was observed. Mean time to progression in
`all patients (n = 26) included was 22 weeks. The drug was
`generally well
`tolerated (Table 3). Fourteen of the 26
`patients had no registered side-effect. Troublesome fatigue
`was observed in 2 patients. The treatment was stopped for
`both, and the fatigue decreased. In one of the patients (a
`PR) the drug was reintroduced and the symptom worsened
`again. All other possible side-effects were only tentatively
`associated with the treatment. The treatment was not
`
`stopped in the patient with the deep venous thrombosis, as
`the condition was not considered to be related to the
`Droloxifene treatment.
`
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`DROLOXIFENE IN ADVANCED BREAST CANCER
`
`427
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`Table 2
`
`Response rate and duration
`
`Treatment result
`
`No.
`
`0
`4
`5
`13
`4
`
`”0
`
`0
`15.4
`19.2
`50
`15.4
`
`Median duration
`(weeks) of
`response (range)
`
`27 (7752)
`57 (35767)
`
`( <4 weeks)
`22 (mean)
`
`CR
`PR
`NC
`PD
`Not evaluable
`TTF (n = 26)
`
`Table 3
`
`Registered side-efl‘ecls
`
`Patients without side—effects
`Nausea
`Fatigue'
`Vertigo
`Constipation
`Deep venous thrombosis
`Hot flushes
`
`Weight gain
`Reactive depression
`Initial pelvic pain
`
`n
`
`l4
`3
`2
`2
`1
`I
`1
`
`1
`1
`1
`
`'Fatigue, caused withdrawel of medication
`in both patients (one of these PR, 7 weeks).
`
`Discussion
`
`Important characteristics of tamoxifen are its long half-
`life and its estrogenic/antiestrogenic etTects. This last char-
`acteristic is, at least partially, dependent on the amount of
`endogenous estrogens offered to the target cells. The drug
`could be beneficial in postmenopausal women with regard
`to its estrogenic effects on lipid (12. 13) and bone mineral
`(14, 15) metabolism. However, adverse effects on the en-
`dometrium have been reported (16). Furthermore, the long
`half-life of tamoxifen at least partly precludes trials with
`new schedules to explore alternating endocrine treatment
`(17), and continuous versus intermittent treatment (18).
`Droloxifene has a short half-life in humans (8, 9),
`is
`
`reported to be less estrogenic (10), and also in animals
`seems to have less carcinogenic potential in the liver (19).
`The results from the present study indicate that the drug
`can be safely used in humans, and that about one-third of
`this heterogenous group of patients experienced a meaning-
`ful effect. It is interesting that 3 of the 4 responders were
`resistant to tamoxifen when starting with Droloxifene.
`The fatigue seen in 2 patients seems to be related to the
`treatment.
`In both patients the medication had to be
`stopped. This side-effect has not been reported so far in 15
`
`patients included in our new Droloxifene trial, and has not
`been reported as a problem in other trials (20422).
`This is the first report from a phase II trial of Drolox-
`ifene, using 100 mg once daily. In another phase II study
`(19) a response rate of 17% (4/23) was observed with
`Droloxifene 80 mg once daily, and 29"” (4/14) using
`120 mg daily. Two large phase II dose-finding studies are
`under way (21, 22), comparing 20, 40 or 100 mg once
`daily. It seems reasonable to explore further the potential
`role of Droloxifene in the treatment of breast cancer.
`
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