review
`
`Annals of Oncology 17: 200-204, 2006
`doi:10.1093/annonc/mdi047
`Published online 26 October 2005
`
`Fulvestrant, a new treatment option for advanced
`breast cancer: tolerability versus existing agents
`
`l. Vergote“ & P. Abram2
`’Unlversi'ty Hospitals, Leuven, Belgium; 2Belvoi'r Park Hospital, Belfast, UK
`
`Received 17 April 2005; revised 10 September 2005; accepted 12 September 2005
`
`E
`.9>
`
`as3_
`
`Owing to its favourable tolerability profile versus cytotoxic chemotherapy, endocrine therapy is the treatment of
`choice for postmenopausal women with hormone receptor—positive advanced breast cancer (ABC). However,
`tolerability concerns associated with some endocrine treatments and the potential for cross—resistance has
`helped to drive the need for new, effective and better—to|erated agents. Fulvestrant is a new type of oestrogen
`receptor antagonist with no agonist effects. In phase III trials, fulvestrant has been shown to be at least as effective
`as the third—generation aromatase inhibitor (Al) anastrozole in the treatment of postmenopausal women with ABC
`progressing on prior tamoxifen therapy. Fulvestrant is administered as a once—month|y 250 mg intramuscular
`injection into the gluteus muscle. Here we review the tolerability of fulvestrant in the treatment of postmenopausal
`women with hormone—sensitive ABC and compare it with that of the four most frequently prescribed endocrine
`treatments for advanced disease (tamoxifen, anastrozole, letrozole and exemestane). Compared with these
`agents, fulvestrant is well tolerated and is associated with a lower incidence of joint disorders compared with the
`non—steroidal Als and none of the potential androgenic side—effects that are sometimes seen with steroidal Als.
`It is also associated with hot flushes compared with tamoxifen. Fulvestrant therefore provides clinicians and
`patients with a useful, well—tolerated option for the treatment of hormone—sensitive ABC. Integration of such
`agents into the endocrine treatment sequence may extend the opportunity for using well—tolerated therapies
`before chemotherapy needs to be considered and thus may improve quality of life for patients with ABC. The
`overall safety profiles of newer agents such as fulvestrant will become increasingly clear with their ongoing use.
`Key words: breast, breast cancer, fulvestrant, hormone, neoplasms, therapy
`
`introduction
`
`For patients with advanced breast cancer (ABC) in whom
`palliation of symptoms and maintenance of quality of life are
`the primary objectives, it is important that any treatment is
`well tolerated to aid compliance and treatment success. Owing
`to its favourable tolerability profile, endocrine therapy is the
`treatment of choice for postmenopausal women with hormone
`receptor—positive ABC (i.e. about 73% of the total
`postmenopausal ABC population). Currently available
`endocrine treatments for advanced disease include the
`
`selective oestrogen receptor (ER) modulator tamoxifen, the
`third—generation, non—steroidal aromatase inhibitors (AIs)
`anastrozole and letrozole, and the steroidal AI exemestane.
`The most recent addition to the armamentarium of endocrine
`
`agents is fulvestrant, a novel ER antagonist with no agonist
`effects [1]. It binds, blocks and degrades the ER, thereby
`downregulating cellular ER levels, which in turn leads to
`reduced expression of the progesterone receptor.
`
`*Correspondence to: Dr I. Vergote, University Hospitals Leuven, Department of
`Gynecologic Oncology, Gasthuisberg, Herestraat 49, B—3000 Leuven, Belgium.
`Tel: +32—t6—34—46—35; Fax: +32—t6—34r46—29;
`E—rnail.
`|gnace.Vergote@uz.l<uleuven.ac.be
`
`© 2005 European Society for Medical Oncology
`
`Here we review the tolerability profile of fulvestrant [250 mg
`once monthly, intramuscular (i.m.) injection], and compare it
`with tolerability data from the four most frequently prescribed
`endocrine treatments for ABC: tamoxifen (20 mg once daily,
`orally), anastrozole (1 mg once daily, orally), letrozole (2.5 mg
`once daily, orally) and exemestane (25 mg once daily, orally).
`
`fulvestrant
`
`oestrogen agonist activity
`In a phase I trial involving 30 healthy postmenopausal women,
`volunteers received a single dose of 125 or 250 mg fulvestrant or
`placebo i.m. followed 2 weeks later by 20 mg/day
`ethinyloestradiol for 2 weeks. No evidence of agonist activity in
`the endometrium was observed with fulvestrant [2]. In addition,
`when compared with placebo, after 21 days of treatment the
`mean change in oestrogen—stimulated endometrial thickening
`was prevented using 250 mg fulvestrant (1.5 versus 8.1 mm;
`P < 0.001). Therefore, in contrast to tamoxifen, which has
`well—known agonist effects in the endometrium, fulvestrant
`lacks oestrogen agonist effects and so is unlikely to be associated
`with an increased risk of endometrial cancer with long—term use.
`
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`Annals of Oncology
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`comparative tolerability: fulvestrant versus
`anastrozole
`
`Two phase III studies have shown that fulvestrant is at least
`as effective as anastrozole in the treatment of postmenopausal
`women (n = 851) with ABC who have progressed or relapsed
`on prior tamoxifen treatment [3, 4]. This was also borne out in
`the subgroup of patients with visceral metastases [5].
`Study 0020 (n = 451) was an open—label, randomised, parallel-
`group, multicentre study conducted in Europe, South Africa
`and Australia, in which fulvestrant was delivered in a single 5 ml
`i.m. injection. The median duration of follow—up in this study
`was 14.4 months [4]. Study 0021 (n = 400) was a double—blind,
`randomised, multicentre, parallel—group study conducted in
`North America in which fulvestrant was delivered in two
`
`X 2.5 ml i.m. injections. The median duration of follow—up in
`this study was 16.8 months [3]. Overall, the median duration
`of treatment for both studies was 5.5 months (range 0.9—36.8)
`in the fulvestrant group and 5.5 months (range 0.6—31.4) in the
`anastrozole group.
`Both studies were prospectively designed to allow combined
`analysis of data [6]. Combined analysis of the safety data showed
`that both treatments were well tolerated and there was a low
`incidence of withdrawals due to adverse events (AEs) overall
`(fiilvestrant, 2.8%; anastrozole, 1.9%) and those AEs considered
`to be drug related (fiilvestrant, 0.9%; anastrozole, 1.2%). The
`most common AEs in these trials were nausea (26% versus
`25.3%), asthenia (22.7% versus 27.0%), pain (18.9% versus
`20.3%), vasodilatation (dizziness, light—headedness,
`symptomatic hypotension) (17.7% versus 17.3%) and headache
`(15.4% versus 16.8%) in the fulvestrant and anastrozole groups,
`respectively [6] . In these studies, seven AEs considered relevant
`to endocrine therapy were pre—defined for statistical analysis. In
`both trials, there was no statistically significant difference
`between treatment groups in the incidence of weight gain,
`thromboembolic disease, gastrointestinal disturbance, hot
`flushes or urinary tract infections (Figure 1). However, there
`was a significantly lower incidence of joint disorders (including
`arthralgia, arthrosis and arthritis) with fiilvestrant (5.4%)
`compared with anastrozole (10.6%) (P = 0.0036) (Figure 1).
`The effect of fulvestrant on lipid variables was also monitored
`as part of laboratory investigations in these trials; no major
`changes in lipid variables occurred with either treatment
`(AstraZeneca, data on file). In an extended follow—up for
`time to death, conducted when 75% of patients had died,
`no long—term safety concerns were apparent [7].
`Fulvestrant i.m. injection was well tolerated locally; in most
`cases injection—site reactions were non—serious, mild and
`transient: only 4.6% and 1.1% of fulvestrant i.m. injections in
`trials 0021 and 0020, respectively resulted in injection—site
`events. Across the two studies, only two patients (0.5%) in the
`fulvestrant group withdrew because of injection—site events. In
`a comparison of fulvestrant and placebo injections in trial 0021,
`there was no difference in the incidence of injection—site
`reactions, demonstrating that the fulvestrant i.m. injection is
`well tolerated in contrast to some other injectable anticancer
`agents such as the steroidal AI formestane. For example, in
`a phase II dose—finding study, formestane treatment (500—1000
`mg monthly) resulted in injection—site events (abscesses, painful
`
`Figure 1. The incidence of predefined adverse events in a combined analysis
`of two phase III trials comparing fulvestrant with anastrozole as second—line
`treatments in patients with advanced breast cancer [6]. Reprinted by
`permission of Wiley—Liss, Inc., a subsidiary of Iohn Wiley 8: Sons, Inc.
`
`lumps and allergic—type reactions) in 19% of patients [8].
`To date, there have been no head—to—head clinical studies
`comparing fulvestrant with either letrozole or exemestane.
`
`comparative tolerability: fulvestrant versus
`tamoxifen
`
`A double—blind, double—dummy randomised phase III trial has
`shown that fulvestrant has similar efficacy to tamoxifen in the
`first—line treatment of postmenopausal women (n = 587) with
`hormone receptor—positive ABC [9]. The median duration of
`treatment in this study was 8.3 months (range 0.9—26.5) in the
`fulvestrant group and 9.3 months (range 0.9—25.1) in the
`tamoxifen group.
`At a median follow—up of 14.5 months, the most frequent
`AEs in both groups were nausea (20.3% fulvestrant versus
`22.5% tamoxifen), asthenia (19.4% versus 20.3%),
`vasodilatation (14.8% versus 21.4%), pain (13.9% versus
`19.2%) and bone pain (13.9% versus 17%) [9]. Most AEs
`were mild or moderate in severity. A total of 129 (41.6%)
`patients in the fulvestrant group and 139 (51.3%) patients in
`the tamoxifen group experienced drug—related AEs. The most
`frequent drug—related AEs in both treatment groups were
`vasodilatation, injection—site pain and nausea.
`Of the AEs prospectively defined for statistical comparison,
`there were no significant differences between the two treatment
`groups for vaginitis and thromboembolic disease. There was
`a trend for fewer gastrointestinal disturbances (nausea,
`vomiting, diarrhoea and constipation) with fulvestrant (37.1%
`versus 43.2%; P = 0.16) and the incidence of hot flushes was
`lower in the fulvestrant group than in the tamoxifen group
`(17.7% versus 24.7%; P = 0.05) (Figure 2). The latter
`observation may be related to the fact that fiilvestrant does
`not cross the blood—brain barrier (AstraZeneca, data on file).
`
`tamoxifen
`
`Tamoxifen is generally well tolerated, although with long—term
`use its partial oestrogen agonist properties increase the risk of
`endometrial cancer. In an overview of the randomised trials
`
`of adjuvant tamoxifen including data for 37 000 women, the
`
`P=0.53
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`El Anastrozole
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`P=fl.(X)36
`45
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`P=0.06
`18
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`P#}.6B
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`iL_o.51
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`Urinarytract
`infection
`
`Joint
`disorders
`
`111romboembo|ic Vaginitis
`disease
`
`T d T nm em
`
`P=o.35
`
`Weight
`gain
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`Volume 17 ] No. 2 | February 2006
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`doi:10.1093/annonc/mdj047 | 201
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`steroidal AI exemestane is also associated with arthralgia. In
`a recent phase III study comparing the efficacy and tolerability
`of this steroidal AI with tamoxifen, 11% of exemestane—treated
`patients experienced arthralgia compared with 5% of those
`treated with tamoxifen [19].
`The most common AEs associated with anastrozole are
`
`transient gastrointestinal disturbances, generally mild—to—
`moderate in intensity, headache, asthenia, bone pain and hot
`flushes [20, 21]. The tolerability profile of letrozole appears to be
`broadly similar to that of anastrozole with the most commonly
`encountered AEs also including nausea/vomiting, headache,
`asthenia, bone pain and hot flushes [16, 22]. In the only study
`to compare directly the efficacy and tolerability of anastrozole
`and letrozole, there were no significant differences in the
`incidence of any AEs [23].
`The most frequently reported drug—related AEs with
`exemestane treatment are hot flushes, nausea and fatigue [24].
`Exemestane has weak androgenic properties and has been
`associated with androgenic side—effects such as weight gain,
`alopecia and acne, particularly when used at higher doses [25].
`In a phase III trial comparing the efficacy and tolerability of
`exemestane (25 mg/day) and megestrol acetate (160 mg/day),
`the incidence of grade 3 or 4 weight gain after a median of
`only 17 weeks’ treatment was 8% in the exemestane group
`and 17% in the megestrol acetate group (P = 0.001) [26].
`Androgenic side—effects such as hair loss, hypertrichosis,
`hoarseness and acne are more commonly reported with higher
`doses of exemestane, occurring in 10% of patients treated
`with a 200 mg daily dose [27]. In two short—term trials using
`25 mg/day exemestane, hypertrichosis and acne were reported
`in ~2% of patients [28] and grade 2/3 skin disorders were
`reported in 8% of patients (no reports in the tamoxifen group)
`[18]. In a recent phase III trial, alopecia was reported in 4% of
`patients receiving exemestane 25 mg/day compared with 1% of
`those receiving tamoxifen [19].
`Compared with tamoxifen, exemestane treatment was also
`associated with a higher incidence of increased gamma—glutarnyl
`transferase (33% versus 26%), increased alkaline phosphatase
`(26% versus 14%), increased bilirubin (11% versus 3%),
`dyspnoea (17% versus 11%) and AEs of the skin (19% versus
`14%), whereas hot flushes (29% versus 24%), bone pain (22%
`versus 17%), nausea (21% versus 14%) and oedema (20% versus
`10%) were all more common in tamoxifen—treated patients [18].
`In a subsequent phase III study, exemestane was associated with
`a higher incidence of weight gain (19% versus 14%), arthralgia/
`myalgia (11% Versus 5%) and diarrhoea (9% Versus 3%)
`compared with tamoxifen. In this study, constipation
`(13% versus 8%) and vaginal discharge (7% versus 2%)
`were more commonly seen in patients receiving tamoxifen [19].
`
`summary
`
`More than 1100 postmenopausal women have received
`fulvestrant during the clinical study programme. This new
`endocrine agent exhibits a predictable tolerability profile that
`may offer benefits compared with other agents including
`tamoxifen and the three currently available AIs: anastrozole,
`letrozole and exemestane. In all the phase III trials in
`postmenopausal women with locally advanced or metastatic
`
`50 —
`
`50 —
`
`30 —
`
`20 —
`
`'0 _
`0 _
`
`I Fulvestrant
`Tamoxlfen
`
`P=0.16
`
`117
`
`115
`
`P=o.o5o1
`67
`
`Gastrointestinal
`distubances
`
`Hot flushes
`
`P=°25
`P=0.22
`18
`1 7
`If I:
`Vaginitis
`Thromboembolic
`disease
`
`A 40 _
`,;
`
`$7
`
`U 5
`
`UE
`
`79
`
`Figure 2. The incidence of predefined adverse events in a phase III trial
`comparing fulvestrant with tamoxifen as first—line treatments in patients
`with advanced breast cancer [9]. Reprinted with permission from the
`American Society of Clinical Oncology.
`
`incidence of endometrial cancer was doubled in trials of 1 or
`
`2 years’ treatment and approximately quadrupled in trials of
`5 years’ tamoxifen [10]. Tamoxifen treatment may stimulate
`‘tumour flare’ subsequent to an initial response and is also
`associated with hot flushes and an increased risk of stroke
`
`and thromboembolic disease. In a trial comparing anastrozole
`with tamoxifen in the first—line treatment of ABC, tamoxifen
`was associated with a significantly higher incidence of
`thromboembolic events (6.5% versus 3.6%; P = 0.0434) and
`vaginal bleeding was also reported in fewer anastrozole—treated
`patients (2.2% versus 1%) [11]. The incidence of
`thromboembolic events in a trial comparing tamoxifen with
`letrozole was 2% and 1%, respectively [12]. The agonist activity
`of tamoxifen may, however, have beneficial effects on bone
`mineral density, particularly with long—term treatment,
`e.g. in the adjuvant setting [13].
`
`aromatase inhibitors
`
`Third—generation AIs are effective and generally well tolerated
`in the treatment of postmenopausal women with ABC. The
`selective non—steroidal AIs anastrozole and letrozole have been
`
`shown to be at least as effective as tamoxifen in this setting and
`anastrozole was associated with significantly fewer
`thromboembolic events than tamoxifen [11, 14]. The AIs inhibit
`endogenous oestrogen synthesis via aromatase, which in
`postmenopausal women results in Very low plasma levels of
`oestrogen, and these agents may therefore be associated with
`some deleterious effects on bone [15].
`Joint disorders (e.g. arthralgia) have also been reported for
`all of the third— generation AIs [6, 16-19]. For example, in a trial
`comparing the efficacy and tolerability of letrozole and
`megestrol acetate in patients with ABC, arthralgia was
`experienced by more letrozole—treated patients (13.2%)
`compared with those receiving the comparator treatment
`(7.9%) [16]. However, in a phase III comparative trial of
`letrozole and tamoxifen there was no difference in the incidence
`
`of arthralgia (16% versus 15%, respectively) [14]. As previously
`stated, significantly more anastrozole—treated patients
`experienced joint disorders compared with fulvestrant (10.6%
`versus 5.4%; P = 0.0036) in comparative phase III trials [6]. The
`
`202 | Vergote & Abram
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`Annals of Oncology
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`breast cancer fulvestrant was well tolerated; AEs were generally
`mild or moderate in intensity. The higher incidence of joint
`disorders with the Als compared with fulvestrant illustrates
`the value of fulvestrant in a patient population who may be
`predisposed to musculoskeletal conditions.
`Fulvestrant has no proliferative effect on the endometrium
`[2] and is therefore unlikely to lead to an increased risk of
`endometrial cancer following long—term exposure such as that
`produced by tamoxifen [29]. There have been no reports of
`adverse events that may be attributable to androgenic activity
`and fulvestrant is associated with a lower incidence of hot
`
`flushes compared with tamoxifen. In contrast to other
`endocrine agents used in the treatment of ABC, fulvestrant is
`administered as a once—monthly i.m. injection.
`In summary, fulvestrant 250 mg once—monthly i.m. injection
`is a well—tolerated and effective treatment for postmenopausal
`women with hormone—sensitive ABC. The tolerability profile
`and route of administration of fulvestrant may also lead to
`improved patient compliance and thus better patient outcomes,
`although some patients may prefer to receive their breast cancer
`treatment orally [30]. The previously demonstrated lack of
`cross—resistance of fiilvestrant with other endocrine treatments
`
`along with its favourable tolerability profile means that this
`agent provides clinicians and patients with a useful additional
`option for the treatment of hormone—sensitive ABC. Whilst the
`overall safety profiles of newer endocrine treatments will
`become increasingly clear with their ongoing use, the
`integration of agents such as fulvestrant into the endocrine
`treatment sequence may extend the opportunity for using
`well—tolerated therapies before chemotherapy needs to be
`considered and thus may improve quality of life for patients
`with advanced disease. In addition, the good tolerability profile
`of fulvestrant may suggest possible benefits for this agent in the
`adjuvant setting where longer—term use would be anticipated.
`Although as yet unproven, clinical trials of fulvestrant in the
`adjuvant setting are being planned.
`
`acknowledgements
`
`Editorial assistance was provided by Dawn Batty PhD, with
`financial support from AstraZeneca.
`
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