1 Breast Center at Baylor College of Medicine, Houston, USA; 2 Regional Cancer Centre, Trivandrum, Kerala; 3 Kidwai Memorial Institute, Bangalore, Karnataka, India
Received 15 May 2002; revised 12 August 2002. accepted 19 September 2002
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Abstract |
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More efficacious and safer hormonal agents are needed for breast cancer treatment and prevention. Idoxifene is a novel selective estrogen receptor modulator (SERM) that, in preclinical models, has greater antiestrogenic but lower estrogenic activity than tamoxifen.
Patients and methods:
Three hundred and twenty-one postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer were randomized to receive either tamoxifen or idoxifene as initial endocrine therapy for advanced disease. Data were analyzed based on intention to treat and all the responses were subject to independent review.
Results:
At the time of a second planned interim analysis, the trial was stopped for economic considerations, not for reasons related to safety or efficacy. Complete data for the 219 patients included in the second interim analysis are fully available and reported here. Median age was 59.1 years for idoxifene patients and 59.9 years for tamoxifen patients. Complete response (CR) plus partial response (PR) rates were as follows: tamoxifen, 9%; idoxifene, 13% (P = 0.39). Clinical benefit rate [CR + PR + stable disease (SD) 6 months] was 34.3% for idoxifene and 38.7% for tamoxifen (P = 0.31). Median time to progression and duration of response were 140 days and 151.5 days, respectively, for tamoxifen compared with 166 days and 218 days for idoxifene. None of these endpoints was significantly different for the two drugs, nor was survival. Adverse events (lethal, serious but not lethal and important but not life threatening) were similar in the two arms.
Conclusions:
Idoxifene was both active and well tolerated in postmenopausal women with metastatic breast cancer. Idoxifene had similar efficacy and toxicity to tamoxifen in this randomized comparison.
Key words: advanced breast cancer, clinical trial, endocrine therapy, hormone therapy, idoxifene, tamoxifen
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Introduction |
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Idoxifene (pyrrolidino-4-iodofamaxifene), a 4-iodinated analog of tamoxifen, is a novel selective estrogen receptor modulator (SERM) that was created in an effort to produce an antiestrogen with greater antiestrogenic but lower estrogenic activity than tamoxifen [6, 7]. Compared with tamoxifen, idoxifene has been found to be metabolically more stable [6, 8] and to have a higher relative binding affinity for the estrogen receptor (ER) [7, 9]. Idoxifene has greater in vitro antitumor activity than tamoxifen [7, 10]. In animal models, idoxifene has reduced agonist activity on the uterus [7, 11] and is less likely to develop drug resistance [12]. Furthermore, it produces fewer hepatic DNA adducts than tamoxifen [13, 14] and can retard bone loss and lower cholesterol levels [11].
There are limited data on idoxifenes activity in human breast cancer. In a phase I study, 20 patients with advanced breast cancer were treated with idoxifene, 19 of which had previously received tamoxifen. Two patients demonstrated partial response (PR) (including one who had received prior tamoxifen) and four additional patients had stable disease for 656 weeks [15]. In a phase II study of 56 postmenopausal patients comparing idoxifene 40 mg/day and tamoxifen 40 mg/day, idoxifene was associated with clinical activity in patients with tamoxifen-resistant advanced breast cancer. Similar safety profiles were seen with both compounds [16]. Furthermore, in a study that explored the efficacy of idoxifene in breast cancer through modulation of biological markers in patients with primary breast cancer scheduled for surgery, idoxifene produced a significant antiproliferative effect in ER-positive breast cancer as demonstrated by a decrease in the K67 labeling index, but no effect in ER-negative cancers [17].
Because of the favorable preclinical findings and promising phase I and II data and because better SERMs are needed, a double-blind, multicenter, randomized study to compare the efficacy and toxicity of idoxifene with tamoxifen was initiated. This trial was open to postmenopausal women with ER-positive or progesterone receptor (PgR)-positive or ER/PgR-unknown tumors with measurable or assessable metastatic breast cancer.
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Patients and methods |
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Treatment
Patients randomized to receive idoxifene took one 20 mg idoxifene tablet and one 40 mg idoxifene tablet daily for the first 21 days (loading dose of 60 mg/day), followed by one 40 mg idoxifene tablet per day (maintenance dose) for the duration of the study.
Patients randomized to receive tamoxifen took one 20 mg tamoxifen and one placebo tablet daily for the first 21 days, followed by one 20 mg tamoxifen tablet per day for the duration of the study.
Patient and disease assessment
Baseline screening assessment completed within 4 weeks before randomization included demographic information, complete history and clinical examination including body weight and performance status [ECOG/World Health Organization (WHO) scale]. Diagnostic imaging studies for complete disease assessment included the following: X-ray, computed tomography (CT) or magnetic resonance imaging (MRI) scan of the chest, liver evaluation by imaging, radionuclide bone scan, mammography and other scans if clinically indicated. Blood was collected for hematology and blood chemistries. There must have been identification of at least one indicator lesion and a maximum of five indicator lesions to be used for assessment of response. Indicator lesions must have met criteria for measurable or evaluable disease and must have been assessed using chest X-ray, CT or MRI scan, nuclear scan for bone lesions or photograph for skin lesions. On day 1 (the date of randomization), eligible patients underwent a complete physical examination. Each patients disease was then assessed clinically every 4 weeks for the first 24 weeks of treatment and then every 12 weeks until objective evidence of disease progression was obtained. Where possible, all assessment was repeated at the end of trial therapy. Trial treatment continued until objective disease progression was observed, at which time it was stopped. Further treatment was left to the discretion of the investigator and follow-up was performed until death. Patients could be withdrawn from active treatment for the following reasons: objective disease progression, occurrence of a serious adverse event, protocol violation (including non-compliance), unwillingness to continue the trial or withdrawal at the investigators discretion. All patients were followed at regular intervals (at least every 3 months, if possible) after withdrawal from the study to determine survival.
Tolerability assessment
An adverse event was defined as any detrimental change in a patients condition after randomization and during any follow-up period, unless considered by the investigator to be related to disease progression. All adverse events were recorded, irrespective of whether the event was considered to be related to the trial therapy. Toxicity was expressed as the worst Common Toxicity Criteria (CTC) grade experienced by the patient for the study (patient incidence). A serious adverse experience was defined as any event which was fatal, life-threatening, permanently or temporarily disabling or incapacitating, or resulted in hospitalization, prolonged a hospital stay, or was associated with a congenital abnormality, new cancer or overdose (either accidental or intentional).
Target sample size
The primary objective of the study was to compare the two groups of treatment. Assuming a 30% response rate to tamoxifen, to detect a difference of 10% in response rate, using a two-sided test, = 0.05 and a power of 0.85 (ß = 0.15), 400 evaluable patients (200 per arm) would be needed. Target enrollment for this study was 440 patients, allowing for a 10% drop-out rate.
Method of randomization
Patients were randomized by a fixed schedule, using a centrally generated list of random assignments to one of two blinded treatment regimens. Patients were randomized with equal probability to receive tamoxifen or idoxifene. The randomization schedule employed the technique of randomly permuted blocks.
Planned efficacy evaluations
The primary efficacy variables were the response rate (RR), defined as the proportion of the total of evaluable patients who achieved a complete or partial response (PR), and the time to progression (TTP).
Measurable disease was defined as the presence of bidimensionally measurable lesions with clearly defined margins by diagnostic studies (CT or MRI scan or ultrasound or chest X-ray) with at least one diameter 2 cm, or a palpable lymph node lesion with at least one diameter
2 cm, preferably verified by an imaging procedure. A skin lesion was required to have one diameter
1 cm confirmed by photograph with scale.
Evaluable but not measurable disease included unidimensional measurable lesions, lytic bone lesions, lesions with margins that were not clearly defined, palpable lesions with largest diameter 2 cm, or hepatomegaly.
Complete response (CR) was defined as a complete disappearance of all known measurable and evaluable disease determined by two measurements not less than 4 weeks apart. Partial response in measurable disease was defined as a decrease 50% in the sum of the products of the greatest length and perpendicular width of all measurable lesions for at least 4 weeks with no simultaneous increase (
25%) in a known lesion, appearance of new lesions or increase in evaluable disease during this period. Partial response was not defined in evaluable disease.
The main secondary efficacy parameters were duration of response (DR) and overall survival (OS). Duration of response was calculated from the date of the initial documented response, the first sign of disease progression being scored as an event, with censoring of other patients at the time of last follow-up or death. Overall survival was also calculated from the date of first treatment, death being scored as an event with censoring of other patients at the time of last follow-up. Another secondary efficacy variable was the tolerability of treatment with idoxifene and tamoxifen.
Methods of analysis
Descriptive statistics and standard 2 test and Fishers exact test were used to evaluate safety data. All comparisons were based on the principle of intention to treat. Standard
2 test and Fishers exact test were performed to compare demographic and baseline clinical characteristics. A standard
2 test was also employed to determine whether the response rate associated with idoxifene differed significantly from that associated with tamoxifen. Two-sided values of P <0.05 were considered statistically significant.
Times to event endpoints were compared between treatments. Survival curves were derived from KaplanMeier estimates [18]. The curves were compared by the log-rank test [19]. Survival rates and relative risks (RR) are presented with their 95% confidence intervals (CI).
The design of this study included two planned interim analyses. These analyses were to be conducted 16 weeks after 25% and 50% of the target sample had been enrolled. The interim decision rule was based on the response rate, and employed the alpha adjustment strategy described by Fleming et al. [20].
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Results |
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Patient characteristics
Data for the 219 patients included in the second interim analysis are displayed in Table 1. The groups were well balanced with respect to both pretreatment characteristics and prior cancer therapy. The patients in this study, all female, were predominantly Indian (42.9%) or Caucasian (34.2%). Mean age was 59.1 years for idoxifene patients and 59.9 years for tamoxifen patients, with a range from 30 to 90 years. Mean weight was 60.9 kg for idoxifene patients and 60.4 kg for tamoxifen patients. Demographic characteristics were similar for the two treatment groups.
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Important but non-life threatening, related or possibly related adverse experiences that occurred at any time on study were prospectively assessed as part of the protocol (Table 6). The majority of these adverse experiences for both treatment groups were relatively mild (grades 1 and 2). Except for leukorrhea, there was no statistically significant difference in frequency in the two arms. Leukorrhea was reported in four patients treated with idoxifene, but in none with tamoxifen (P = 0.05).
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Discussion |
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Currently, the most widely used hormonal treatment for breast carcinoma is the antiestrogen tamoxifen. From its first successful application in the therapy for patients with advanced breast carcinoma [21], the use of tamoxifen now extends to first-line treatment for patients with advanced disease [21, 22] and to adjuvant treatment for patients with primary breast carcinoma [23, 24]. The success of tamoxifen is based on the beneficial combination of therapeutic efficacy and a modest level of side effects. Tamoxifen has also shown benefit as a preventive agent [2528]. Therefore, the potential use of antiestrogen therapy now spans the gamut of breast cancer therapy, ranging from prevention to the treatment of advanced disease. Although the benefits of tamoxifen in the treatment of breast cancer are well established, approximately one-third to one-half of ER-positive breast cancers fail to respond to it. Most will eventually become resistant to tamoxifen, and a few will even become dependent on it for growth [5]. Additionally, there are a number of adverse effects associated with tamoxifen including endometrial cancer, clotting events, hot flushes and vaginal discharge or dryness. Thus, though tamoxifen is clearly beneficial and generally well tolerated, there remains a need to discover drugs that are potentially more efficacious or have fewer side effects than tamoxifen. In an effort to further these goals, this trial was designed to compare the efficacy and tolerability of idoxifene, a new derivative from the triphenylethylene structure of tamoxifen, to tamoxifen in postmenopausal patients with metastatic breast cancer. Primary indicators of efficacy were response rate and progression-free interval, with secondary indicators being survival, response duration and tolerability of treatment. The response rate (complete plus partial) of 9% and the progression-free interval of 140 days for tamoxifen-treated patients were not statistically different from the response rate of 13% and the progression-free survival of 166 days for idoxifene-treated patients. Clinical benefit rate for tamoxifen was 38% compared with 34% for idoxifene. Neither the duration of response nor overall survival differed significantly between the tamoxifen and idoxifene groups. Both therapies were well tolerated. Major adverse reactions resulting in mortality or discontinuation of therapy were rare in both treatment arms.
Tamoxifen has previously been shown to be associated with a slightly increased risk of thrombotic events when compared with patients not on hormone therapy [29, 30]. In preclinical models and in one clinical trial including osteopenic postmenopausal women [31], idoxifene showed a beneficial effect on vessel wall injury [32] and cholesterol levels [11]. This was expected to have implications for clinical benefit. There were slightly more vascular complications (myocardial infarction, pulmonary embolism, peripheral gangrene, left cardiac failure) among idoxifene-treated patients (2.5%) than among tamoxifen-treated patients (0.6%). Although cardiac arrest and myocardial infarction observed in two idoxifene-treated patients were considered unlikely to be related to study medication, the present data do not suggest a favorable vascular protective effect of idoxifene.
Tamoxifen has been associated with a two- to three-fold increase in risk of endometrial cancer in women treated in the adjuvant setting [3335]. Preclinical evidence showed that idoxifene had no agonist activity on the uterus [11]. A double-blind placebo-controlled trial involving 331 osteopenic postmenopausal women who were treated with either placebo or idoxifene (2.5 mg/day or 10 mg/day) for 12 weeks indicated that idoxifene was associated with an increase in endometrial thickness and polyps, as evaluated by transvaginal sonography. Though abnormal pathologic changes of the endometrium were extremely rare in the treated group [36], there was an unexpected and unexplained increased incidence of uterine and pelvic prolapse in idoxifene-treated women. In the present trial, no increased incidence of uterine prolapse or polyps was observed and no endometrial cancer was detected at the time of analysis in both the treatment arms. Since all patients on trial had metastatic breast cancer, the long-term potential for uterine carcinogenicity of idoxifene cannot be assessed.
Other triphenylethylenic antiestrogens, such as droloxifene [37, 38] and toremifene [39, 40], have been tested clinically and described in the literature. Both of these drugs have a similar structure to tamoxifen, differing only by the addition of one chlorine atom at position 4 in the toremifene molecule and the addition of a hydroxy group in the droloxifene molecule [41]. To date, none of these has been proven to offer significant advantages over tamoxifen in terms of either efficacy or tolerability. In addition, the likelihood of cross-resistance between these agents and tamoxifen may limit their application in patients with advanced disease after adjuvant tamoxifen treatment [37, 42]. So far, the strategy of modestly altering the triphenylethylenic backbone in an attempt to produce antiestrogens with superior efficacy or side-effect profiles compared with tamoxifen has not proven successful in the treatment of breast cancer.
Considering the wide range of current and newly available hormonal therapies, it will be necessary to demonstrate therapeutic superiority or a better toxicity profile for a new antiestrogen to justify the continued development of the compound. This study, as well as the study by Johnston et al. [43], was unable to demonstrate or suggest such superiority for idoxifene and therefore development was discontinued. Rather than focusing on a strategy of simply altering the triphenylethylenic backbone, future development of drugs that act on the estrogen receptor pathway should focus on molecules that have substantially different structures or mechanisms of action, such as the pure antiestrogen fulvestrant, or on drugs that target other parts of the estrogen response pathway or related pathways, such as Iressa®.
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Acknowledgements |
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Footnotes |
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