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PubMed2002

FDA drug approval summaries: fulvestrant.

Patients with hormone-sensitive breast cancer who have responded to tamoxifen may receive additional benefit from a second endocrine agent following progression or relapse after tamoxifen therapy. Fulvestrant (Faslodex((R)), ICI 182780, AstraZeneca Pharmaceuticals; Wilmington, Delaware) is a selective antagonist of estrogen designed to have no estrogenic effects. Lack of aqueous solubility led to the development of a parenteral formulation for monthly intramuscular administration. Fulvestrant has been shown to inhibit the proliferative effects of estrogen on sensitive tissues in vitro and in vivo, and is without apparent measurable estrogenic activity. The data upon which marketing approval for fulvestrant was based are summarized below. Eight hundred fifty-one postmenopausal women with advanced breast cancer were enrolled in two phase III studies, 400 in a North American double-blind study and 451 in a European open-label study, comparing the efficacy and safety of fulvestrant with anastrozole. Four hundred twenty-eight patients were randomized to receive fulvestrant 250 mg monthly by intramuscular injection and 423 patients were to receive anastrozole 1 mg daily. Patients were considered hormone sensitive either by receptor status or previous response to endocrine therapy. Over 96% of patients had previously received tamoxifen, either in the adjuvant setting or as treatment for metastatic disease. The primary study end points were response rate and time to progression. Response rates for patients treated with fulvestrant were 17% and 20% in the North American and European trials, respectively, compared with 17% and 15% in the anastrozole treatment arms. There were no statistically significant differences in response rates, time to progression, or survival between treatment arms in either study. The most common adverse events attributed to the treatment (>10%) were injection-site reactions and hot flashes. Common events (1%-10%) included asthenia, headache, and gastrointestinal disturbances (nausea, vomiting, and diarrhea), as well as rash and urinary tract infections. A small increase in joint disorders was reported in the anastrozole-treated patients. On April 25, 2002, fulvestrant 250 mg by monthly intramuscular injection was approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Approval was based on similarity of response rates and time to progression between fulvestrant and anastrozole.

Antineoplastic Agents, Hormonal↗

PubMed2005

Current and future perspectives on fulvestrant.

Fulvestrant, an estrogen receptor antagonist with no known agonist effects, is effective and well tolerated in the treatment of hormone-sensitive breast cancer after antiestrogen failure in postmenopausal women. Numerous phase II and III clinical trials of fulvestrant that are designed to build on its efficacy in breast cancer and explore its value in other tumors are ongoing or in the final planning stage. Favorable safety, dose-response, and pharmacokinetic data led to the initiation of clinical trials to evaluate loading and higher doses with the aim of building on the well-defined efficacy of fulvestrant. Recently reported results of phase II trials by the North Central Cancer Treatment Group and the Swiss Group for Clinical Cancer Research support the clinical activity of fulvestrant after recurrence or progression on a nonsteroidal aromatase inhibitor, and 2 international phase III trials are ongoing in this setting. As a first-line treatment for metastatic disease, fulvestrant is currently being evaluated in combination with anastrozole versus anastrozole alone in 2 phase III trials, 1 by the Southwest Oncology Group and the other being conducted mainly in Scandinavia. Preclinical data have also led to randomized phase II trials of fulvestrant in combination with the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib, and the HER2/neu-targeted antibody trastuzumab. Additional phase II and III trials are currently evaluating fulvestrant plus tipifarnib, Theratope vaccine, or the dual kinase inhibitor, GW572016. Although fulvestrant is undergoing robust clinical development as a treatment for breast cancer, investigation of this agent in other types of solid tumors has only just begun.

Anastrozole↗

PubMed2006

Cooperative effect of gefitinib and fumitremorgin c on cell growth and chemosensitivity in estrogen receptor alpha negative fulvestrant-resistant MCF-7 cells.

The selective ER downregulator, fulvestrant, is currently approved as a second line endocrine therapy after onset of resistance to prior antiestrogen therapy in postmenopausal breast cancer patients. Resistance to antihormonal therapies is common and, therefore, we anticipate that fulvestrant-resistance will occur as well. The current study was undertaken to investigate the underlying molecular changes after fulvestrant-resistance and find new therapeutic targets and agents for fulvestrant-resistant breast cancer cells. We developed a unique fulvestrant-resistant cell line (MCF-7/F), derived from MCF-7 estrogen receptor alpha (ERalpha)-positive human breast cancer cells, by culturing them in 1 microM fulvestrant containing medium for approximately 18 months. MCF-7/F cells became irreversibly ERalpha negative as withdrawal of fulvestrant did not alter the ERalpha-negative phenotype, determined by real-time PCR, Western blot analysis, and ERE-luciferase transfection assays. MCF-7/F cells grew in a hormone-independent manner. Interestingly, MCF-7/F cells overexpressed both epidermal growth factor receptor (EGFR) and breast cancer resistant protein (BCRP). Gefitinib, a specific EGFR tyrosine kinase inhibitor, preferentially inhibited the growth of MCF-7/F cells relative to MCF-7 cells by inhibiting both MAPK44/42 and Akt phosphorylation. MCF-7/F cells became less sensitive to chemotherapeutic agents such as mitoxantrone. Moreover, fumitremorgin C, a specific BCRP inhibitor, significantly increased the efficacy of mitoxantrone in MCF-7/F cells. Gefitinib increased the inhibitory effect of mitoxantrone on cell growth. Similarly, fumitremorgin C increased the inhibitory effect of gefitinib on cell growth, suggesting that there is a bidirectional crosstalk between EGFR and BCRP. More importantly, these results provide a molecular basis for using gefitinib, BCRP inhibitors, and chemotherapeutic agents as combination therapy approaches in fulvestrant-resistant breast cancer.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2005

Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials.

BACKGROUND: Fulvestrant is an estrogen receptor antagonist with no agonist effects. In the second-line treatment of advanced breast carcinoma, fulvestrant was shown previously to be as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to disease progression and objective response rates. The authors reported the overall survival results from these studies. METHODS: A prospectively planned, combined, overall survival analysis was performed, including data from two Phase III trials that compared the efficacy and tolerability of fulvestrant (250 mg monthly; n = 428) with anastrozole (1 mg daily; n = 423) in the treatment of postmenopausal women with advanced breast carcinoma who had disease progression after receipt of previous endocrine treatment. RESULTS: At an extended median follow-up of 27.0 months (range, 0-66.9 months), 319 (74.5%) patients in the fulvestrant group and 322 (76.1%) patients in the anastrozole group had died. Prolonged survival was observed with both drugs, with 10-20% of patients still alive > 5 years after randomization. The median overall survival was similar between treatments, being 27.4 months and 27.7 months in fulvestrant and anastrozole-treated patients, respectively (hazards ratio, 0.98; 95% confidence interval, 0.84-1.15; P = 0.809). Fulvestrant continued to be well tolerated, and was associated with a significantly lower incidence of joint disorders compared with anastrozole (P = 0.0234). CONCLUSIONS: The current analysis showed that fulvestrant was similar to anastrozole with respect to overall survival in the second-line treatment of postmenopausal women with advanced breast carcinoma.

Anastrozole↗

PubMed2004

Response to fulvestrant in heavily pretreated postmenopausal women: a single-center experience.

Fulvestrant ('Faslodex') is a new estrogen receptor (ER) antagonist that has no agonist effects. It binds, blocks and accelerates degradation of the ER, leading to a complete abrogation of estrogen-sensitive gene transcription. In postmenopausal women with advanced breast cancer progressing on prior endocrine therapy, fulvestrant is at least as effective as the third-generation aromatase inhibitor (AI) anastrozole. In this single-center experience, 42 postmenopausal patients with metastatic breast cancer who had been heavily pretreated with prior endocrine therapy and chemotherapy were treated with fulvestrant. Prior endocrine therapies included selective ER modulators (including tamoxifen and toremifene), AIs, megestrol acetate, and high-dose estrogens. In total, eight patients (19%) achieved stable disease (SD) for > or =24 weeks, including two patients with SD for 2 years and one with SD for 14 months. Fulvestrant was well tolerated with the majority of adverse events related to the site of metastatic disease. These data demonstrate that fulvestrant is a well tolerated and effective endocrine therapy for postmenopausal women with metastatic breast cancer who have been heavily pretreated with prior therapies. The novel mechanism of action of fulvestrant reduces the likelihood of cross-resistance with other endocrine therapies and therefore this agent may be active in patients who have proved to be resistant to treatments such as tamoxifen or AIs. The use of fulvestrant earlier in the sequence of endocrine treatments may achieve better responses than observed in this heavily pretreated patient population.

Adult↗

PubMed2005

Sensitivity to further endocrine therapy is retained following progression on first-line fulvestrant.

There is a need for new endocrine agents that lack cross-resistance with currently available treatments to extend the endocrine treatment window and delay the need for cytotoxic chemotherapy. This retrospective analysis evaluated the response of postmenopausal patients with previously untreated metastatic/locally advanced breast cancer to further endocrine treatment following progression on first-line fulvestrant or tamoxifen. Patients received fulvestrant 250 mg (intramuscular injection every 28 days) plus matching tamoxifen placebo (once daily), or tamoxifen 20 mg (orally once daily) plus matching fulvestrant placebo (every 28 days) in a double-blind, randomized, phase III trial. Treatment continued until disease progression or withdrawal, when further endocrine therapy was initiated (at the treating physician's discretion). Information regarding subsequent therapies and responses was obtained by follow-up questionnaire. Two-hundred-and-forty-five questionnaires were returned (from 587 patients), 149 of which yielded follow-up data on patients receiving second-line endocrine therapy following fulvestrant (n=83) and tamoxifen (n=66). Second-line therapy produced objective responses (OR) in 6/44 (13.6%) and clinical benefit (CB) in 25/44 (56.8%) patients who had CB with fulvestrant and produced OR in 5/41 (12.2%) patients and CB in 27/41 (65.8%) patients who had CB with first-line tamoxifen. For patients deriving no CB from trial therapy, second-line therapy produced OR in 3/39 (7.7%) and CB in 15/39 (38.5%) patients in the fulvestrant group and OR in 4/25 (16.0%) and CB in 12/25 (48.0%) patients in the tamoxifen group. Results from this questionnaire-based study suggest that postmenopausal women with advanced breast cancer who respond to first-line fulvestrant or tamoxifen retain sensitivity to subsequent endocrine therapy.

Adult↗

PubMed2006

Fulvestrant ('Faslodex'): current and future role in breast cancer management.

Fulvestrant ('Faslodex') is a new type of estrogen receptor antagonist with no agonist effects, that reduces cellular levels of both estrogen and progesterone receptors. Results from two Phase III trials showed that fulvestrant is at least as effective as the third-generation selective aromatase inhibitor anastrozole in postmenopausal women with advanced breast cancer following progression on antiestrogen therapy, indicating the potential for second-line fulvestrant in this setting. In clinical practice, fulvestrant is well tolerated, with good rates of clinical benefit observed as first-line therapy and following progression on prior endocrine agents. Other endocrine agents have been shown to have good clinical activity when resistance to fulvestrant has developed, showing that fulvestrant lacks cross-resistance with other treatments. Ongoing trials are investigating the efficacy of fulvestrant after failure on aromatase inhibitors and evaluating its use in combination with therapies that target growth factor receptor signaling pathways.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

A comparison of fulvestrant and the third-generation aromatase inhibitors in the second-line treatment of postmenopausal women with advanced breast cancer.

Fulvestrant, a new type of oestrogen receptor antagonist with no agonist effects, is now licensed in the EU and USA for the treatment of postmenopausal women with hormone-sensitive advanced breast cancer following progression on prior antioestrogen therapy. Approval was based on data from two phase III trials that demonstrated fulvestrant was at least as effective as the third-generation aromatase inhibitor (AI) anastrozole as a second-line treatment for advanced breast cancer. The third-generation AIs letrozole and exemestane also demonstrate efficacy after tamoxifen failure. To compare the performance of fulvestrant and contemporary endocrine treatments (anastrozole, letrozole and exemestane) in tamoxifen-resistant disease, we conducted a literature review using the PubMed database. These indirect comparisons suggest that fulvestrant offers similar efficacy and tolerability to other second-line treatments for postmenopausal women with advanced breast cancer. Findings from these comparisons support the use of fulvestrant as an additional second-line endocrine treatment option in this setting. New trials are assessing the efficacy of fulvestrant as a second-line treatment following AI failure. The integration of new agents such as fulvestrant into the endocrine sequence may extend the endocrine treatment window, before cytotoxic chemotherapy needs to be considered, and therefore improve patient quality of life.

Aged↗

PubMed2003

Pharmacokinetics of a single dose of fulvestrant prolonged-release intramuscular injection in postmenopausal women awaiting surgery for primary breast cancer.

OBJECTIVE: The aim of this study was to describe the pharmacokinetics of 3 different single doses of fulvestrant-a new estrogen receptor (ER) antagonist that downregulates the ER with no known agonist effects-administered as a prolonged-release IM formulation. METHODS: Pharmacokinetic data were obtained in a randomized, partially blinded, placebo-controlled, parallel-group, Phase I/II multicenter trial involving postmenopausal women with primary breast cancer (clinical stages T1-T3, with tumors that were ER positive or of unknown ER status) awaiting curative-intent surgery. Patients received either IM fulvestrant (50, 125, or 250 mg), oral tamoxifen (20 mg, once daily), or oral placebo (once daily). Treatment started 2 to 3 weeks before surgery and blood was taken at various times up to 12 weeks after fulvestrant administration to assess pharmacokinetic variables. RESULTS: A total of 200 patients entered the trial, of whom 58 took part in the pharmacokinetic analysis (50 mg, n = 20; 125 mg, n = 16; 250 mg, n = 22). Following single IM injections of fulvestrant, the median time to maximum concentration was 6.98, 6.98, and 6.96 days in the 50-, 125,- and 250-mg dose groups, respectively, with an overall range of 2 to 19 days). The plasma concentration-time profiles were primarily controlled by the rate of absorption from the injection site; post-peak plasma concentrations declined over time and were measurable up to 84 days after administration of fulvestrant 125 and 250 mg. Plasma concentrations at 28 days were 2- to 5-fold lower than the maximum value. Plasma concentration data for the 250-mg dose were best described by a 2-compartment pharmacokinetic model, with an apparent terminal phase half-life of approximately 49 days, beginning approximately 3 weeks after administration. Mean area under the plasma concentration-time curve for days 0 through 28 (AUC 0-28) was proportional for fulvestrant 50, 125, and 250 mg. For a doubling of the dose, an analysis of covariance model of the pharmacokinetic data projected an estimated increase in AUC 0-28 of a factor of 1.84 (95% CI, 1.67 to 2.04). CONCLUSIONS: The IM formulation of fulvestrant used in this study had predictable, dose-linear pharmacokinetics. The prolonged-release properties of this formulation suggested that it may be well suited for the once-monthly dosing schedule intended for clinical use.

Aged↗

PubMed2003

Postmenopausal women who progress on fulvestrant ('Faslodex') remain sensitive to further endocrine therapy.

PURPOSE: This retrospective evaluation of data from two randomized, multicenter trials examined whether tumor responses to further endocrine therapy were seen in postmenopausal women with advanced breast cancer who had progressed on both initial endocrine therapy, usually tamoxifen, and on the estrogen receptor (ER) antagonist fulvestrant ('Faslodex'). PATIENTS AND METHODS: A combined total of 423 patients received fulvestrant 250 mg as a monthly intramuscular injection. After progression on fulvestrant, some patients received another endocrine therapy. Responses to subsequent endocrine therapy were assessed using a questionnaire sent to the trial investigators. Best responses were classified as a complete or partial response (CR or PR), stable disease (SD) lasting > or = 24 weeks, or disease progression. RESULTS: Follow-up data were available for 54 patients who derived clinical benefit (CB, defined as CR, PR or SD) from fulvestrant and who received subsequent endocrine therapy, resulting in a PR in 4 patients, SD in 21 patients, and disease progression in 29 patients. Data were available for 51 patients who derived no CB from fulvestrant and who received further endocrine therapy, resulting in a PR in 1 patient, SD in 17 patients, and disease progression in 33 patients. Aromatase inhibitors were used as subsequent endocrine therapy in > 80% of patients. CONCLUSIONS: After progression on fulvestrant, patients may retain sensitivity to other endocrine agents. Fulvestrant provides an additional option to existing endocrine therapies for the treatment of advanced or metastatic breast cancer in postmenopausal women, and may provide the opportunity to extend the sequence of endocrine regimens before cytotoxic chemotherapy is required.

Adult↗

PubMed2005

Fulvestrant, a new treatment option for advanced breast cancer: tolerability versus existing agents.

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-tolerated 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 (AI) anastrozole in the treatment of postmenopausal women with ABC progressing on prior tamoxifen therapy. Fulvestrant is administered as a once-monthly 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 AIs and none of the potential androgenic side-effects that are sometimes seen with steroidal AIs. 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.

Anastrozole↗

PubMed2004

Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial.

PURPOSE: To evaluate the efficacy and tolerability of fulvestrant (Faslodex; AstraZeneca Pharmaceuticals LP, Wilmington, DE), a new estrogen receptor (ER) antagonist that downregulates ER and has no agonist effects, versus tamoxifen, an antiestrogen with agonist and antagonist effects, for the treatment of advanced breast cancer in postmenopausal women. PATIENTS AND METHODS: In this multicenter, double-blind, randomized trial, patients with metastatic/locally advanced breast cancer previously untreated for advanced disease were randomly assigned to receive either fulvestrant (250 mg, via intramuscular injection, once monthly; n = 313) or tamoxifen (20 mg, orally, once daily; n = 274). Patients' tumors were positive for ER (ER+) and/or progesterone receptor (PgR+), or had an unknown receptor status. RESULTS: At a median follow-up of 14.5 months, there was no significant difference between fulvestrant and tamoxifen for the primary end point of time to progression (TTP; median TTP, 6.8 months and 8.3 months, respectively; hazard ratio, 1.18; 95% CI, 0.98 to 1.44; P =.088). In a prospectively planned subset analysis of patients with known ER+ and/or PgR+ tumors ( approximately 78%), median TTP was 8.2 months for fulvestrant and 8.3 months for tamoxifen (hazard ratio, 1.10; 95% CI, 0.89 to 1.36; P =.39). The objective response rate for the overall population was 31.6% with fulvestrant and 33.9% with tamoxifen, and 33.2% and 31.1%, respectively, in the known hormone receptor-positive subgroup. Both treatments were well tolerated. CONCLUSION: In the overall population, between-group differences in efficacy end points favored tamoxifen, and statistical noninferiority of fulvestrant could not be demonstrated. However, in patients with hormone receptor-positive tumors, fulvestrant had similar efficacy to tamoxifen and was well tolerated.

Administration, Oral↗

PubMed2004

Fulvestrant - a new treatment for postmenopausal women with hormone-sensitive advanced breast cancer.

Approximately 75% of breast tumours in postmenopausal women are positive for the oestrogen receptor (ER) and/or the progesterone receptor (PgR) and are, therefore, potential candidates for endocrine treatment. Fulvestrant is a new type of ER antagonist with no agonist effects and a novel mode of action; it binds, blocks and degrades the ER, leading to a reduction in cellular ER and, consequently, in PgR levels. This novel mode of action results in a lack of cross-resistance with other commonly used endocrine treatments. In Phase III trials in postmenopausal women with advanced breast cancer progressing on prior anti-oestrogen therapy, fulvestrant was at least as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to progression and objective response, and was associated with similar overall survival. In the first-line setting, fulvestrant showed similar efficacy to tamoxifen in patients with ER-positive and/or PgR-positive disease. Efficacy in more heavily pretreated patients has also been demonstrated in the fulvestrant compassionate use programme. Fulvestrant is well tolerated, being associated with a significantly lower incidence of joint disorders compared with anastrozole, and a lower incidence of hot flushes compared with tamoxifen. Fulvestrant, therefore, provides clinicians with a useful additional treatment for hormone-sensitive advanced breast cancer in postmenopausal women. Ongoing trials will help to clarify the optimal position of fulvestrant in the endocrine treatment sequence for these patients.

Antineoplastic Agents, Hormonal↗

PubMed2002

The oncology nurse's role in educating patients on endocrine therapy for metastatic breast cancer--focus on fulvestrant.

Fulvestrant, an estrogen receptor downregulator, is an effective and a safe endocrine option for postmenopausal women with advanced breast cancer who progress or develop recurrent disease on prior endocrine therapy. The recommended dose is 250 mg given as a single 5-mL or 2 concurrent 2.5-mL monthly intramuscular injections. Common adverse events associated with fulvestrant are hot flashes, nausea, and mild injection site reactions. Applying warm or cold compresses to the injection site can minimize injection site reactions. In randomized double-blind clinical trials, the frequency of injection site reactions for fulvestrant are no different from the comparator (anastrozole) arm. Overall, fulvestrant has a safety profile similar to aromatase inhibitors. Advantages of this agent are its effectiveness in tamoxifen-resistant tumors and the lack of agonistic property, creating a favorable side-effect profile. One limitation is that there is no evidence regarding the safety and effectiveness of fulvestrant in premenopausal women. Among endocrine therapies used to treat breast cancer, fulvestrant is unique not only in its mechanism of action but also in its mode of administration. With oral therapies, the patient fills the prescription in a pharmacy and takes the medication home. In contrast, with monthly fulvestrant intramuscular injection, the patient will have increased contact with the nurse. The increased interaction between the patient and the nurse will affect the role of nurses providing patient education and monitoring.

Administration, Oral↗

PubMed2001

Fulvestrant.

Fulvestrant is a 7alpha-alkylsulphinyl analogue of estradiol that competes with endogenous estrogen for binding to the estrogen receptor. Once bound to the receptor, fulvestrant attenuates receptor dimerisation, effecting a rapid degradation of the estrogen receptor protein and inhibition of transcription. Fulvestrant is a potent inhibitor of the growth of human breast cancer cells in vitro and in vivo. It has demonstrated pure anti-estrogenic activity in animal systems. Intramuscular fulvestrant 250 mg once a month was as effective as the oral aromatase inhibitor anastrozole 1 mg/day in 2 phase III trials in postmenopausal women with advanced breast cancer who had received prior endocrine therapy. Median time to disease progression (the primary end-point) with fulvestrant and anastrozole was 5.4 and 3.4 months (North American trial) and 5.5 and 5.1 months (European trial). The median duration of response was 19.3 and 10.5 months (North American trial) and 14.3 and 14.0 months (European trial). The most common adverse events with fulvestrant are gastrointestinal disturbances and hot flushes. Fulvestrant showed similar tolerability to anastrozole in 2 phase III trials.

Antineoplastic Agents, Hormonal↗

PubMed2003

Equivalent single-dose pharmacokinetics of two different dosing methods of prolonged-release fulvestrant ('Faslodex') in postmenopausal women with advanced breast cancer.

PURPOSE: To compare the pharmacokinetics of two different dosing methods of fulvestrant ('Faslodex'), an estrogen receptor antagonist with no known agonist activity, for the treatment of advanced breast cancer. METHODS: Postmenopausal women with advanced breast cancer were randomly assigned to receive a single 5-ml intramuscular injection of 250 mg fulvestrant, or two 2.5-ml intramuscular injections with a total of 250 mg fulvestrant. Blood samples were taken for pharmacokinetic analysis up to 28 days after injection. RESULTS: Plasma concentrations of fulvestrant were measurable up to 28 days after both dosing methods. The concentration-time profiles were relatively shallow, spanning an approximate threefold range from 3 h after dosing to Cmin measured on day 28. Peak plasma concentrations (Cmax) of fulvestrant occurred between 1 and 11 days after dosing, with mean Cmax values of 6.0 and 6.2 ng/ml following one 5-ml injection and two 2.5-ml injections, respectively. The plasma concentration-time profiles were very similar in terms of duration and concentration, and overall exposure to fulvestrant was similar in both dosing groups (the ratio of the AUC(0-28) of the single-injection group to that of the double-injection group was 1.01; 95% confidence interval 0.68-1.51). CONCLUSION: This study found no evidence of any pharmacokinetic difference between one 5-ml injection and two 2.5-ml injections. The two methods can be used interchangeably, depending on which is more convenient in any particular clinical setting.

Aged↗

PubMed2005

Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance.

Understanding the underlying mechanisms responsible for endocrine resistance remains a challenge in improving the treatment of breast cancer. The discovery that growth factor and estrogen receptor (ER) signaling pathways interact in endocrine resistant breast cancer has provided a rationale for disrupting these signaling cascades in ER-positive, endocrine-resistant tumors. In postmenopausal women, the ER signaling pathway may be targeted using fulvestrant ('Faslodex'), a new type of ER antagonist with no agonist effects. Fulvestrant binds, blocks and causes degradation of the ER, culminating in complete abrogation of estrogen-sensitive gene transcription. This unique mechanism of action may result in a lack of cross-resistance with other endocrine agents. Preclinical studies have confirmed the potential of fulvestrant to inhibit the growth of tamoxifen-resistant, as well as tamoxifen-sensitive, human breast cancer cell lines. Clinical studies have demonstrated that fulvestrant is an effective treatment option in postmenopausal women with advanced breast cancer who have progressed on prior endocrine therapy. Furthermore, preclinical studies indicate that combining fulvestrant with growth factor targeted agents, such as the epidermal growth factor receptor (EGFR/HER1) tyrosine kinase inhibitor gefitinib (IRESSA) or the anti-human HER2 monoclonal antibody trastuzumab ('Herceptin'), may result in greater anti-tumor activity than either agent alone. A range of clinical trials are now ongoing to determine whether the combination of growth factor-targeting agents with fulvestrant will delay the onset of endocrine resistance and so provide new strategy for women with hormone receptor-positive advanced breast cancer.

Antineoplastic Agents, Hormonal↗

PubMed2006

Effects of fulvestrant 250mg in premenopausal women with oestrogen receptor-positive primary breast cancer.

Fulvestrant (Faslodex) reduces markers of hormone sensitivity and proliferation in postmenopausal women. This Phase II double-blind, randomised, multicentre study compared the effects of a single 250mg intramuscular dose of fulvestrant and placebo 14-21 days prior to surgery of curative intent on the oestrogen receptor (ER), progesterone receptor and Ki67 levels in 66 premenopausal women with ER-positive primary breast cancer. There were no statistically significant differences between fulvestrant and placebo with respect to any of the three markers analysed. The most common adverse events in both groups were nausea, headache and pyrexia. Fulvestrant 250mg had no effects on markers of hormone-sensitivity and proliferation in premenopausal women with primary breast cancer when measured at 14-21 days after injection. These findings suggest that a higher fulvestrant dose may be required in this patient population. Further clinical trials are necessary to evaluate the efficacy of fulvestrant in premenopausal women.

Adult↗