Breast Cancer Research and Treatment 29: 223~228, 1994.
`© 1994 Kluwer Academic Publishers. Printed in the Netherlands.
`
`Report
`
`High dose toremifene in advancedbreast cancerresistant to or relapsed
`during tamoxifen treatment
`
`Seppo Pyrhénen,' Ritva Valavaara,’ Jouni Vuorinen’ and Alajos Hajba?
`‘ Department ofRadiotherapy and Oncology, Helsinki University Central Hospital:? Department of
`Radiotherapy and Oncology, Turku University Central Hospital; and? Orion Corporation Farmos,
`R & D Pharmaceuticals
`
`Key words: advancedbreast cancer, antiestrogenic therapy, tamoxifen resistance, second-line treatment,
`toremifene
`
`Summary
`
`Fifty patients with advanced breast cancer refractory to prior tamoxifen therapy were assigned to investiga-
`tional treatment with high-dose toremifene administered 120 mgorally twice a day. Treatment wasgenerally
`well tolerated. The majority (80%) of the patients hadnoside effects, and among the remaining10 patients
`reported side effects were mostly mild and/or transient. Two objective tumor responses were observed: one
`complete response (CR), duration 6.2 months, and one partial response (PR), duration 8 months. The re-
`sponse rate was thus 4% (95% CI: 0.5 to 14%). In addition 3 patients experienced a mixed response, some
`metastatic sites responding, while at other sites disease progressed; 22 patients haddiseasestabilization for > 2
`months. A subset analysis disclosed that a small subgroupof patients, including7 patientsin this study, who
`had achieved CR at someof the sites during preceding tamoxifen therapy, experienced a long progression-
`free time during high dose toremifene treatment. The mediantimeto progressionin this subgroupof patients
`was 9.4 months (95% CI: 3.8 to 9.4) as opposed to 2.1 months (95% CI: 2.0 to 2.8) for all the remaining 43
`patients, whichis a significant decrease in disease progression (p < 0.03). Such results reveal that althoughthis
`kind of second-line hormonaltreatmentwith high dose toremifene cannot be recommendedforall tamoxifen
`failures, there mightbea subsetof patients,ie. those who achieve CR in somelesion during tamoxifen ther-
`apy, who benefit from this type of treatment.
`
`Introduction
`
`Toremifene is a chlorinated triphenylethylene de-
`rivative, chemically related to tamoxifen. At least
`five different phase III trials comparing tamoxifen
`with toremifene in postmenopausal patients with
`breast cancer are currently underway or under
`analysis [1]. In preclinical studies some differences
`have been observed between tamoxifen and tore-
`
`mifene in efficacy as well as in toxicity in favor of
`toremifene[2]. Especially in high doses, toremifene
`has been less toxic both in animal experiments [2]
`andin clinical phaseIJ [3, 4] and II studies [5—7]. Dai-
`ly doses up to 240 mg have been well tolerated even
`during prolonged treatment[5-7]. Also some dose-
`responserelationship has been observed in animal
`model tumors, high doses of toremifene being more
`effective than low and moderate doses [2]. Even es-
`
`Address for offprints: S. Pyrhénen, Department of Radiotherapy and Oncology, Helsinki University Central Hospital, Haartmaninkatu
`4, SF-00290 Helsinki, Finland
`
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`224
`
`‘S$ Pyrhénen etal.
`
`trogen-receptor (ER)-negative tumorslike murine
`uterine sarcoma have responded to high doses of
`toremifene [2]. The subsequent phase II clinical
`studies as primary hormonaltreatment in advanced
`breast cancer also reveal existence of some dose-
`response relationship, the highest response rate
`(over 60% ) being achieved with a 240 mgdaily dose
`[6] while a 20 mg daily dose has yielded only a 21%
`responserate in similar patients [8, 9]. All these ob-
`servations have focused interest on high dose tore-
`mifene as a second- or third-line treatment in ad-
`vanced breast cancer for tamoxifen-refractory pa-
`tients. Preliminary observations from the UK.re-
`vealed that high-dose toremifene might be an
`effective second-line treatment for such patients
`[10]. Consequently this confirmatory study was ini-
`tiated to provide more knowledgeof the feasibility
`of high-dose toremifene as second-line treatment
`for patients with advanced breast cancer resistant
`to tamoxifen or patients relapsed during tamoxifen
`therapy.
`
`Patients and methods
`
`Patients
`
`in prognostically less favorable
`vanced disease,
`sites. Four patients were treated previously with ad-
`juvant chemotherapy. Twenty-four patients haddis-
`ease progression during adjuvant tamoxifen treat-
`ment and 26 patients during the treatment of ad-
`vanced disease. Median disease free interval among
`these two groups of patients was 20.2 and 30.0
`months, respectively. This difference wasnotstatis-
`tically significant (p = 0.3, Mann-Whitneytest).
`
`Treatment
`
`Toremifene was administered as 120 mg orally
`twice a day. Toremifene treatment was started im-
`mediately (next day) after cessation of tamoxifen
`therapy. The treatment was discontinuedonsigns of
`progressive disease, or intolerable side effects, or
`according to the patient’s desire.
`
`Evaluation
`
`The pretreatment evaluation included physical ex-
`
`Table I. Patient characteristics
`
`Patients entered
`Evaluable
`
`50
`48
`
`Median PR (range)
`
`62.0 fmol/mg prot
`(11-921)
`39.0 fmol/mg prot
`(0-1502)
`
`
`
`Fifty consecutive postmenopausal women with ER-
`positive tumors(2 10 fmol/mg prot) were recruited
`68.9 years (40-83)
`Mean age (range)
`into this study between June 1986 and April 1990.
`Mean postmenopausal period (range)—19.0 years (2.5-39.4)
`All had advanced disease: inoperable primary or
`Median Karnofsky index (range)
`80% (50-100)
`metastatic breast cancer progressing during tamox-
`Receptors
`Median ER(range)
`ifen treatment. Prior chemotherapy, except adju-
`vant treatment, was not allowed. Other prerequi-
`sites included performance status = 50% (Karnof-
`sky), life expectancy >3 months, measurable or
`evaluable disease, no evidence of severe heart,liver
`or renal disease nor uncontrolled diabetes. The dis-
`ease could either be primarily resistant to tamoxi-
`fen treatment or relapsed after a response. The
`study was approved bythe local ethical committees
`and verbal informed consent was obtained from all
`the patients. The main patient characteristics and
`localization of lesions are depicted in Table 1.
`Twelve patients had only soft tissue lesions,i.e. cu-
`taneous, subcutaneous, or lymph node metastases,
`while the majority of the patients had more ad-
`
`Localization oflesions (total: 85 sites)
`Primary
`Local relapse
`Soft tissue
`Visceral
`Skeletal
`
`Distribution of lesions in 50 patients
`Onlysoft tissue
`Onlyvisceral
`Visceral + soft tissue
`
`1
`13
`20
`24
`27
`
`12
`8
`3
`
`Only skeletal
`Skeletal + primaryorsoft tissue or
`23
`visceral
`
`
`4
`
`
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`High dose toremifene in tamoxifen-resistant breast cancer—225
`
`Table 2. Overall responses
`
`Response
`No.of patients (%) Time-to-progression,
`in months
`
`
`5.8
`1( 2)
`CR
`8.2
`1(¢ 2)
`PR
`5.5-17.0
`9 (18)
`SD 25 months
`2.8- 4.3
`13 (26)
`SD <5 months
`0.9- 2.3
`24 (48)
`PD
`
`
`2( 4)NE 11+ 1.9
`
`amination, laboratory tests, chest radiography, ul-
`trasonographyof the liver, and bonescan. Patients
`came for clinical assessment every 4 weeks during
`the first 16 weeks and thereafter every 8 weeks. Le-
`sions evaluable by physical examination,routine X-
`rays, or ultrasonography were checked during ev-
`ery visit. Otherwise chest X-rays, ultrasonography
`of the liver, and bone scan were repeated every 6
`months. The tumor response and duration of re-
`sponse were evaluated according to UICCcriteria
`[11]. The evaluation of adverse effects followed the
`World Health Organization guidelines [12].
`
`Statistical analysis
`
`An estimate for the true response rate and an exact
`95% confidence interval for the true response was
`calculated. The distribution of time-to-progression
`was estimated by the Kaplan-Meier method. Median
`times-to-progression with 95% confidence intervals
`(CI) are reported. Kaplan-Meier curves were com-
`
`Table 3. Patients with mixed responses, achievingpartial or com-
`plete responseat anysite
`
`Patient
`Duration of
`Localization
`Response
`treatment (wks)
`
`
`H-15
`
`H-22
`
`T-8
`
`16
`
`8
`
`8
`
`lymph node
`skeletal
`liver
`skeletal
`soft tissue and
`skin
`
`PR
`PD*
`CR
`PD*
`
`PR
`
`pared with a log rank-test. An estimate for the true
`hazard ratio and a 95%CIfor the true hazard ratio
`were calculated in order to assess the difference in
`time-to-progression between the two groups under
`consideration. A hazard ratio of 1 is indicative of
`identical proportions of patients with a subsequent
`eventofinterest such as disease progressionat a giv-
`en time point. A hazard ratio of less than 1 is indica-
`tive that a smaller proportion of patients progressed
`in the first group of patients compared to the second
`group of patients at a given time point.
`
`Results
`
`Response
`
`All 50 patients were evaluable for toxicity. Two pa-
`tients discontinued the treatment in less than 2
`months and were not evaluable for response. The
`antitumor effect of toremifene in all 50 patientsis
`presented in Table 2. There were two objective re-
`sponses; response rate 4% (95% CI: 0.5 to 14%).
`One patient with lung and pleural metastases
`achieved a complete response (CR) of 6.2 months’
`duration. She succumbedto chronic cardiovascular
`disease while in complete remission. The heartdis-
`ease was diagnosedalreadyprior to the toremifene
`treatment, so her death was not considered to be
`attributed to that drug. In anotherpatienta partial
`response (PR) in multiple skin metastases was ob-
`served, duration 8.0 months. In addition to these
`two objective responses, 22 patients (44%) had a
`stable disease (SD) for longer than 2 months. Alto-
`gether 9 of these stabilized diseases remained stable
`longer than 5 months,the longest duration being 17
`months. In addition to the 2 overall objective re-
`sponses, another 3 patients experienced mixed re-
`sponses,i.e. although someofthe lesions regressed,
`the disease progressed in othersites. The metastatic
`sites and the corresponding responses of these
`mixed-responders are presented in Table3.
`
`PD
`lungs
`PD
`liver
`
`
`Time-to-progression
`
`* increasein size oflytic lesion in x-rays.
`
`The median time-to-progression (TTP) ofall the
`
`

`

`
`—— CR in some lesions
`
`---
`
`Remaining Patients 0.8
`
`Probability
`
`0.6
`
`0.4
`
`0.2
`
`been ee
`
`Time to Progression (in months)
`
`Fig. 1. Time-to-progressionin 7 patients with CR in some lesions
`during previous tamoxifen therapyvs.all the remaining 43 pa-
`tients. Differenceis statistically significant (P = 0.03, Log rank-
`test).
`
`treated patients was 2.8 months (95% CI: 2.0 to 3.5).
`Comparison of TTP to the outcomefor previousta-
`moxifen therapy revealed some differences. The
`patients werefirst divided into 5 groups: one group
`suffered progressive disease while receiving adju-
`vant tamoxifen (24 patients), and the other 4 groups
`were defined according to the response of evalua-
`ble metastases during tamoxifen therapy (26 pa-
`tients). As performed elsewhere[13], we selected 5
`months’ TTP as a cut-point of prognostic signifi-
`cance. Differences were as follows: only 3 of 24 pa-
`tients (13%) who experienced relapse during adju-
`vant treatment had TTP over 5 months, in contrast
`to 8 of 26 (31%) patients who received tamoxifen
`for metastatic disease (Table 4). Interestingly,all 3
`patients with CR for all sites and 5 of 7 patients
`
`(71%) with CRat any site during previous tamoxi-
`fen treatment suffered no disease progression be-
`fore 5 months (Table 4). Figure 1 demonstrates the
`differences in probability of managing withoutpro-
`gression amongthe 7 patients who had experienced
`CR in someof the evaluable lesions during previous
`tamoxifen treatmentandall other patients. These 7
`had a median TTP of 9.4 months (95 % CI: 3.8 to 9.4)
`as opposed to 2.1 (95% CI: 2.0 to 2.8) forall the
`other 43 patients. This differenceis statistically sig-
`nificant (x’ = 5.0, p = 0.03, Log rank-test). No other
`apparent factor such as age, length of postmeno-
`pausal period, receptor content, the initial disease
`free interval, or localization of the lesions was asso-
`ciated with this prolongation of TTP.
`
`Toxicity
`
`The treatment was generally well tolerated. Forty
`patients experiencednoside effects, and amongthe
`otherpatients side effects were mainly mild or mod-
`erate (grade I or IT) and sweating mostly only tran-
`sient (Table 5). In 2 cases the treatment was discon-
`tinued within 2 months without evidence of disease
`progression; one of these patients had thrombosis
`in the left thigh, which obviously had beentherepri-
`or to this treatment due to major surgery on that leg
`(prophylactic bone fixation a.m. Ktintscher). The
`otherpatient, 74, experienced a cerebrovascularin-
`sult one monthafter the start of treatment. Relation
`of this event to the treatment cannot be excluded.
`
`
`
`226=S Pyrhdnenetal.
`
`Table 4. Prediction of prolonged time-to-progression (TTP) by response to preceding tamoxifen therapy
`
`No. (%) of patients with TTP over 5 months
`No.of patients
`Tamoxifen treatment and its outcome
`during treatment with toremifene
`
`Adjuvant treatment
`Response of evaluable disease
`PD
`SD
`PR
`CR
`
`24
`
`7
`12
`4
`3
`
`3 (13)
`
`2 (29)
`2 (17)
`1 (25)
`3 (100)
`
`5 (71)
`7
`CRin any of the lesions*
`
`* Including three patients with overall response SD and one with overall response PR.
`
`
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`High dose toremifene in tamoxifen-resistant breast cancer
`
`227
`
`Discussion
`
`In postmenopausal patients with metastatic breast
`cancer, second-line treatment with another hor-
`monal drug is usually feasible when the first-line
`therapyfails. Someclinical [10] and preclinical stud-
`ies [2], particularly, reveal that high dose toremi-
`fene may be active in tumors in which tamoxifen is
`ineffective. Preclinical studies have demonstrated
`that high concentrations of toremifene may have a
`direct receptor-independentoncolyticeffect, i.e. be
`cytostatic or cytotoxic against tumors withoutestro-
`gen receptors [2]. Recently, new estrogen-receptor-
`independent mechanisms of antiestrogens have
`been identified. These molecules are foundto be ef-
`fective inducers of transforming growth factor beta
`(TGF-beta)in fibroblastic cells [13], and TGF-beta
`excreted from stromalfibroblasts has the ability to
`inhibit growth or division of breast cancercells [14].
`The magnitude of this TGF-beta-mediated mecha-
`nism as well as the estrogen-receptor-mediated
`growth-inhibition of breast cancercells are evident-
`ly to a certain extent related to the concentration of
`an antiestrogenic drug [14]. As confirmed in pre-
`clinical [2] as well as phase I andII clinical studies
`[3~7, 10], toremifene seemsto beless toxic than ta-
`moxifen in high doses although therapeutic benefit
`of high doses has not been established. Thus this
`type of high dose second-line treatment was consid-
`ered in principle interesting.
`In two previously published studies, experience
`with high dose toremifene as a second-line treat-
`ment after tamoxifen failure varied widely. A pre-
`liminary report from the U.K. [10] describes a re-
`
`Table 5. Side effects
`
`No.of patients (%)
`
`50
`Evaluable patients
`40 (80)
`Nosideeffects
`6 (12)
`Sweating*
`2( 4)
`Nausea and depression*
`2( 4)
`Dizziness*
`1( 2)
`Thrombosis
`1( 2)
`Fatigue
`
`Leucorrhea* 1( 2)
`
`* All these side effects were mild or moderate and sweating was
`mostly only transient.
`
`markable objective response rate (25%), while in a
`Swedish study no response was reported among 35
`patients [7]. In a recently published study from
`USA 5% (95 CI: 3% to 7%) response rate was de-
`tected [15]. Our observation accords very well with
`that study: two objective responses among 48 eva-
`luable patients,i.e. a response rate of 4%. The great
`difference between the aforementioned studies
`may be explained mainly by differences in patient
`characteristics. In the U.K. study the majority of the
`patients had fairly localized disease and had pri-
`marily responded or exhibited prolongedstabiliza-
`tion under tamoxifen treatment, while in the Nordic
`and USAstudies the patients were less selected ta-
`moxifen failures. A large proportion of the patients
`in the latter studies had received tamoxifen as an
`adjuvant treatment or had never respondedtopri-
`mary tamoxifen treatment. In addition a large pro-
`portion of the patients in these studies had very ex-
`tensive disease including visceral and boneinvolve-
`ment. Therefore the great difference in response
`rates with similar treatment may be expected.
`An objective response rate of 4 percent asin this
`study might be considered clinically non-signifi-
`cant, particularly if the treatment had considerable
`toxicity. The analysis, however, disclosed that 80%
`of the patients had noside effects, and the remain-
`ing 10 patients experienced mostly only mild or
`transient side effects. In this kind of palliative treat-
`ment, besides objective tumor regression, pro-
`longedstabilization of the disease may be meaning-
`ful as well, as suggested by Howell and coworkers
`[16]. They analyzed prognoses of patients with ad-
`vanced breast cancer under endocrine therapy and
`observedthat patients with stabilized disease over 5
`months had prognosesindistinguishable from that
`of those achieving partial response. When analyz-
`ing TTP in the present study, we observed that, in
`addition to the two patients with objective re-
`sponses, another 9 patients were progression-free
`over 5 months and 2 of them even over 12 months.It
`is apparent that most of these patients also bene-
`fited from toremifene treatment.
`In this kind of phase II study, the number of pa-
`tients is a limiting factor for subset analysis. This
`study, however, confirms the observations that the
`outcomeof previous endocrine therapy might be a
`
`
`
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`228
`
`S Pyrhénenetal.
`
`valuable predictor for selecting patients for second-
`line hormonaltreatment[17]. All the three patients
`whoachieved overall CR during preceding tamoxi-
`fen treatment had no disease progression until after
`5 months when changedto high dose toremifene. In
`addition there were 4 other patients who achieved
`CR with tamoxifen in some of their numerous
`metastatic sites. Altogether this subset of 7 patients
`with CR achieved in some location during tamoxi-
`fen treatment hadsignificantly longer time-to-pro-
`gression than did the remaining 43 patients. Al-
`though the figures are small, this should provide
`some interest in this kind of analyses for similar
`other studies as well as subset meta-analysis from
`all the high dose toremifene studies. This manage-
`ment might disclose more clearly a subset of pa-
`tients in whom a second-line antiestrogenic treat-
`ment with high dose toremifene is beneficial, pro-
`viding these patients with another chancefor a non-
`toxic hormonal treatment prior to changing to
`other endocrine therapies or more toxic cytostatic
`drugs.
`
`Acknowledgements
`
`Theskilful secretarial assistance of Ms. Raija Vassi-
`nen is gratefully acknowledged. This investigation
`has been supported by a research grant from the
`Finnish CancerSociety.
`
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