Expert Opinion on Investigational Drugs
ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20
Fulvestrant for the treatment of endometrial cancer Dr. Marco Johannes Battista & Prof. Dr. Marcus Schmidt To cite this article: Dr. Marco Johannes Battista & Prof. Dr. Marcus Schmidt (2016): Fulvestrant for the treatment of endometrial cancer, Expert Opinion on Investigational Drugs, DOI: 10.1517/13543784.2016.1154532 To link to this article: http://dx.doi.org/10.1517/13543784.2016.1154532
Accepted author version posted online: 16 Feb 2016.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieid20 Download by: [Gazi University]
Date: 19 February 2016, At: 20:23
Publisher: Taylor & Francis Journal: Expert Opinion on Investigational Drugs DOI: 10.1517/13543784.2016.1154532 Drug Evaluation: Fulvestrant for the treatment of endometrial cancer
Dr. Marco Johannes Battista1, Prof. Dr. Marcus Schmidt1
Downloaded by [Gazi University] at 20:23 19 February 2016
1
University Hospital Mainz, Department of Obstetrics and Gynecology Langenbeckstr. 1 55131 Mainz GERMANY Corresponding author: Prof. Dr. Marcus Schmidt Langenbeckstr. 1 D-55131 Mainz, Germany Phone: ++49-6131-17-7313 Fax: ++49-6131-17-3291 e-mail: [email protected]
Abstract: Introduction: About one third of patients with endometrial cancer (EC) relapse and face a limited prognosis, if surgery or radiotherapy are not feasible. The remaining therapeutic options are chemotherapy and endocrine therapy. Areas covered: This review summarizes the development of the first selective estrogen receptor (ER) down-regulator fulvestrant. This article provides its mechanism of action, pharmacokinetics and the available preclinical and clinical data. Furthermore, this review provides an overview of the market of treatments for recurrent or metastatic EC (RMEC) while also taking into account studies of fulvestrant in metastatic breast cancer.
Expert opinion: Even if fulvestrant showed only marginal activity in two phase II trials, it shouldn’t be abandoned but instead further developed in EC. Firstly, the dose of fulvestrant used in these trials was too low from today’s point of view. Secondly, the available literature on other endocrine agents is full of limitations and does not provide a gold standard. Furthermore, given the activity of mTOR inhibitors in EC, there may also be synergistic effects, given the cross-regulation of ER and the PI3K/AKT/mTOR pathway. The authors suggest that a prospective, phase II trial in ER positive RMEC would help to further explore
Downloaded by [Gazi University] at 20:23 19 February 2016
the efficacy and tolerability of fulvestrant together with a mTOR inhibitor.
Key words: Chemotherapy,
endometrial
cancer,
estrogen
receptor
antagonist,
fulvestrant,
medroxyprogesterone acetate, megestrol acetate, mTOR inhibitor, selective estrogen receptor downregulator, tamoxifen
List of abbreviations: BC breast cancer; EC endometrial cancer; ER estrogen receptor; MA megestrol acetate; MBC metastatic
breast
cancer;
mTOR
mammalian
target
of
rapamycin;
MPA
medroxyprogesterone acetate; PFS progression free survival; PI3K phosphatidylinositol-4,5bisphosphate-3-kinase; PK pharmacokinetics; RCT randomized controlled trial; RMEC recurrent and metastatic endometrial cancer; RR response rate; OS overall survival
1. Introduction: 1.1. Introduction on endometrial cancer
2
Each year about 320.000 new cases of endometrial cancer (EC) occurs and about 76.000 women die worldwide [1]. The five-year survival rate are approximately 80% [2]. The highest incidence of EC is measurable in the seventh decade of life [2]. As symptoms appear early, the majority of patients are diagnosed in early stages [2]. Whereas the endometrioid EC, designated as type I EC, occurs preferentially in early stages with a favorable prognosis, the serous-papillary, clear cell and other EC, designated as type II EC, present in younger women with advanced stages and recur more often [2]. Surgery is the cornerstone of treatment and
Downloaded by [Gazi University] at 20:23 19 February 2016
helps to stratify patients for further adjuvant radiotherapy and chemotherapy [2]. Adjuvant endocrine treatment is not effective and becoming less frequently used [2,3]. Local recurrence and distant metastasis occur in about one third of the patients. A central recurrence in the pelvis might be curable by surgery and/or radiotherapy with a five year overall survival (OS) rate of 21-60% [4,5]. Patients with pelvic recurrence, who are not suitable for these procedures or who presents with distant metastasis, are faced with a dismal median OS of roughly twelve months and a three year OS rate of 8-14% [6,7]. In these cases, either endocrine or cytostatic therapies are the remaining options [8,9]. However, the available literature is full of controversies and limitations and therefore no real standard of care exists [8,9].
1.2. Overview of the market The Medline database was searched for randomized controlled trials (RCT) and for phase II trials in recurrent and metastatic endometrial cancer (RMEC) testing endocrine, cytostatic and targeted therapies (see tables 1, 2 and 3). In a second step the references of these detected trials were checked for further trials. The majority of the available trials on endocrine treatment were single arm, phase II studies including not more than 100 patients 3
with the exception of a handful, RCT (see table 1 and 2). Moreover, inclusion criteria were broad in terms of histological grade, type of EC and patients’ history (see table 1 and 2). Endocrine treatment should be considered in asymptomatic, hormone receptor positive, grade 1 or grade 2 endometrioid RMEC [8–10]. However, these factors arose out of explorative analyses and were not prospectively validated [11]. Furthermore, adjuvant treatment of EC changed significantly during the last decade, as chemotherapy increasingly replaced radiotherapy [3,12]. In 2013 this development culminated in the introduction of
Downloaded by [Gazi University] at 20:23 19 February 2016
the concept of “platinum sensitivity” to EC in analogy to recurrent ovarian cancer [13]. As many trials of RMEC were conducted before this switch of adjuvant treatment had happened, one might be careful in adopting these results into todays’ treatment decisions. The pattern of care study conducted by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), showed that among German gynecologists and gynecological oncologists progestins were the most popular compound in RMEC followed by tamoxifen, aromatase inhibitors, fulvestrant and a combinational therapy (p
ISSN: 1354-3784 (Print) 1744-7658 (Online) Journal homepage: http://www.tandfonline.com/loi/ieid20
Fulvestrant for the treatment of endometrial cancer Dr. Marco Johannes Battista & Prof. Dr. Marcus Schmidt To cite this article: Dr. Marco Johannes Battista & Prof. Dr. Marcus Schmidt (2016): Fulvestrant for the treatment of endometrial cancer, Expert Opinion on Investigational Drugs, DOI: 10.1517/13543784.2016.1154532 To link to this article: http://dx.doi.org/10.1517/13543784.2016.1154532
Accepted author version posted online: 16 Feb 2016.
Submit your article to this journal
Article views: 1
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieid20 Download by: [Gazi University]
Date: 19 February 2016, At: 20:23
Publisher: Taylor & Francis Journal: Expert Opinion on Investigational Drugs DOI: 10.1517/13543784.2016.1154532 Drug Evaluation: Fulvestrant for the treatment of endometrial cancer
Dr. Marco Johannes Battista1, Prof. Dr. Marcus Schmidt1
Downloaded by [Gazi University] at 20:23 19 February 2016
1
University Hospital Mainz, Department of Obstetrics and Gynecology Langenbeckstr. 1 55131 Mainz GERMANY Corresponding author: Prof. Dr. Marcus Schmidt Langenbeckstr. 1 D-55131 Mainz, Germany Phone: ++49-6131-17-7313 Fax: ++49-6131-17-3291 e-mail: [email protected]
Abstract: Introduction: About one third of patients with endometrial cancer (EC) relapse and face a limited prognosis, if surgery or radiotherapy are not feasible. The remaining therapeutic options are chemotherapy and endocrine therapy. Areas covered: This review summarizes the development of the first selective estrogen receptor (ER) down-regulator fulvestrant. This article provides its mechanism of action, pharmacokinetics and the available preclinical and clinical data. Furthermore, this review provides an overview of the market of treatments for recurrent or metastatic EC (RMEC) while also taking into account studies of fulvestrant in metastatic breast cancer.
Expert opinion: Even if fulvestrant showed only marginal activity in two phase II trials, it shouldn’t be abandoned but instead further developed in EC. Firstly, the dose of fulvestrant used in these trials was too low from today’s point of view. Secondly, the available literature on other endocrine agents is full of limitations and does not provide a gold standard. Furthermore, given the activity of mTOR inhibitors in EC, there may also be synergistic effects, given the cross-regulation of ER and the PI3K/AKT/mTOR pathway. The authors suggest that a prospective, phase II trial in ER positive RMEC would help to further explore
Downloaded by [Gazi University] at 20:23 19 February 2016
the efficacy and tolerability of fulvestrant together with a mTOR inhibitor.
Key words: Chemotherapy,
endometrial
cancer,
estrogen
receptor
antagonist,
fulvestrant,
medroxyprogesterone acetate, megestrol acetate, mTOR inhibitor, selective estrogen receptor downregulator, tamoxifen
List of abbreviations: BC breast cancer; EC endometrial cancer; ER estrogen receptor; MA megestrol acetate; MBC metastatic
breast
cancer;
mTOR
mammalian
target
of
rapamycin;
MPA
medroxyprogesterone acetate; PFS progression free survival; PI3K phosphatidylinositol-4,5bisphosphate-3-kinase; PK pharmacokinetics; RCT randomized controlled trial; RMEC recurrent and metastatic endometrial cancer; RR response rate; OS overall survival
1. Introduction: 1.1. Introduction on endometrial cancer
2
Each year about 320.000 new cases of endometrial cancer (EC) occurs and about 76.000 women die worldwide [1]. The five-year survival rate are approximately 80% [2]. The highest incidence of EC is measurable in the seventh decade of life [2]. As symptoms appear early, the majority of patients are diagnosed in early stages [2]. Whereas the endometrioid EC, designated as type I EC, occurs preferentially in early stages with a favorable prognosis, the serous-papillary, clear cell and other EC, designated as type II EC, present in younger women with advanced stages and recur more often [2]. Surgery is the cornerstone of treatment and
Downloaded by [Gazi University] at 20:23 19 February 2016
helps to stratify patients for further adjuvant radiotherapy and chemotherapy [2]. Adjuvant endocrine treatment is not effective and becoming less frequently used [2,3]. Local recurrence and distant metastasis occur in about one third of the patients. A central recurrence in the pelvis might be curable by surgery and/or radiotherapy with a five year overall survival (OS) rate of 21-60% [4,5]. Patients with pelvic recurrence, who are not suitable for these procedures or who presents with distant metastasis, are faced with a dismal median OS of roughly twelve months and a three year OS rate of 8-14% [6,7]. In these cases, either endocrine or cytostatic therapies are the remaining options [8,9]. However, the available literature is full of controversies and limitations and therefore no real standard of care exists [8,9].
1.2. Overview of the market The Medline database was searched for randomized controlled trials (RCT) and for phase II trials in recurrent and metastatic endometrial cancer (RMEC) testing endocrine, cytostatic and targeted therapies (see tables 1, 2 and 3). In a second step the references of these detected trials were checked for further trials. The majority of the available trials on endocrine treatment were single arm, phase II studies including not more than 100 patients 3
with the exception of a handful, RCT (see table 1 and 2). Moreover, inclusion criteria were broad in terms of histological grade, type of EC and patients’ history (see table 1 and 2). Endocrine treatment should be considered in asymptomatic, hormone receptor positive, grade 1 or grade 2 endometrioid RMEC [8–10]. However, these factors arose out of explorative analyses and were not prospectively validated [11]. Furthermore, adjuvant treatment of EC changed significantly during the last decade, as chemotherapy increasingly replaced radiotherapy [3,12]. In 2013 this development culminated in the introduction of
Downloaded by [Gazi University] at 20:23 19 February 2016
the concept of “platinum sensitivity” to EC in analogy to recurrent ovarian cancer [13]. As many trials of RMEC were conducted before this switch of adjuvant treatment had happened, one might be careful in adopting these results into todays’ treatment decisions. The pattern of care study conducted by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), showed that among German gynecologists and gynecological oncologists progestins were the most popular compound in RMEC followed by tamoxifen, aromatase inhibitors, fulvestrant and a combinational therapy (p
