Fulvestrant

Article Author:
Maheen Farooq
Article Editor:
Shivani Patel
Updated:
8/16/2020 2:01:28 PM
PubMed Link:
Fulvestrant

Indications

Fulvestrant has proven clinical benefit in HR-positive and HER2 negative breast cancer.[1] Endocrine therapy is an important component of management in hormone-positive breast cancer as it is associated with better patient outcomes. Hormone dependent tumors increase in size significantly in the presence of the corresponding hormone in the blood. This pathophysiology provides a potential avenue for treating these cancers. Since about 70 percent of all breast cancers are hormone receptor-positive, these endocrine agents are of utmost importance.

Fulvestrant has been employed in patients with 'advanced' disease, which includes tumors of a very large size or those that metastasize heavily into the lymph nodes. It also includes tumors that have invaded the surrounding tissues and organs.[2] Since management at this stage mainly focuses on providing palliative care, the main objective of this modality of therapy is to improve survival, provide symptomatic improvement, and to enhance the quality of life. 

Fulvestrant is used in combination with several drugs for this purpose e.g., ribociclib, palbociclib, alpelisib, etc.[3][4][5]

Mechanism of Action

Fulvestrant is a novel drug that has shown to be of some use in the management of advanced breast cancer. It acts by binding, blocking, and degradation of estrogen receptors, which in turn, leads to complete cessation of estrogen signaling through the estrogen receptors in the body.[6] Fulvestrant acts as a complete antagonist at the estrogen receptor, as compared with the previously used drugs, namely the selective estrogen receptor modulators (SERMs), for example, tamoxifen, which had partial agonist activity. SERMs blocked the cellular E2 mediated activity of AF-2, which lead to inhibition of transcription downstream. However, they did not have enough AF-1 activity, which possibly leads to their partial agonist activity. Fulvestrant blocks both AF-1 and AF-2, and blocks the transcriptional activities of both downstream, and leaves no room for estrogen to has its effects. Therefore, it is a complete antagonist at the estrogen receptor.[6] 

The novel drug has a high binding affinity for the estrogen receptor, almost 89% of estradiol.[6] It binds tightly with the estrogen receptor and inhibits the dimerization of the receptor, thus inhibiting its nuclear localization. This process forms an unstable nuclear complex, which degrades at a rapid pace and causes disintegration of the estrogen receptor itself. Consequently, in addition to its exclusively antagonistic actions at the estrogen receptor, Fulvestrant also causes accelerated degradation of the estrogen receptors throughout the body, which leads to a decrease in cellular estrogen receptor alpha levels, and also inhibits the estrogen signaling the estrogen receptor itself.[6]

Administration

The mode of administration of fulvestrant is intramuscular. Two injections of 250mg/5mL are injected into the buttocks of the patient (one injection in each), resulting in a cumulative dose of 500mg.[7]

Adverse Effects

Fulvestrant is well-tolerated in most cases, according to multiple clinical trials. The most commonly encountered adverse effects were pain at the injection site and hot flashes. Other common side effects include headache, nausea, vomiting, loss of appetite, constipation, diarrhea, fatigue, and abnormal liver function tests, urinary tract infections, and rashes.[8] In one case study, toxic epidermal necrolysis was observed in a woman with ductal carcinoma of the breast five days after the initiation of fulvestrant.[9]

Another study reported vaginitis, weight gain, joint problems, and thromboembolic problems.[10] In a study investigating the role of palbociclib–fulvestrant in hormone-positive advanced breast carcinoma, various hematological side effects were reported, which included neutropenia, thrombocytopenia, anemia, and leukemia [5]. Vulvovaginal dryness, pelvic pain, and vasomotor symptoms were observations in yet another study.[11] All these side effects are comparable to the previously used endocrine medications such as anastrozole for the treatment of breast cancer. 

Contraindications

Fulvestrant is contraindicated in women who are pregnant or are breastfeeding. It is also associated with an increased bleeding risk in patients who have a clotting disorder and hence is not indicated in these patients. Low platelet count and liver diseases are also contraindications if present in any patient.

Monitoring

The monitoring of blood levels of fulvestrant is not indicated in most patients because, in its usual dosage, it is not known to cause significant adverse effects. No dose adjustment in renal or hepatic impairment is required, and it does not interact with cytochrome 3A4.[12] Regardless, efforts need to be put in this subject to find out the exact therapeutic index and the toxic dose of the medicine so that clinicians may have a sound protocol to administer the drug, even on a trial basis.

Toxicity

An overdose of fulvestrant is not overly likely as its administration must be by a healthcare practitioner. Thus the toxicity that results from the overdose of fulvestrant has not been reported in studies. However, more research is necessary regarding the development of a protocol in case such an event occurs.

Enhancing Healthcare Team Outcomes

Breast cancer is the most common type of carcinoma in women (aside from skin cancers). Fulvestrant is one of the many medications employed in the treatment of breast carcinoma. All patients of breast cancer should be tested for hormone positivity to determine the role of endocrine therapy in their management. A team of healthcare professionals, which includes nurses, lab technologists, pharmacists, and physicians belonging to all related specialties, should coordinate and formulate the best treatment course appropriate for the stage of this type of cancer. 

Interprofessional communication and care coordination will ensure an improvement in patient outcomes and hence should be encouraged and optimized. An essential aspect of the management of breast cancer is the selection of appropriate treatment modalities; this can be by physicians working with other healthcare providers to determine the receptor positivities of the particular tumor. In any case, all patients should receive counseling regarding the clinical benefit and possible toxicities of any medication that the healthcare team deems suitable. 

Multiple trials investigating the effect of fulvestrant in combination with other drugs in patients with hormone-positive breast carcinoma have shown promising results. There is evidence that the 500 mg dose is superior to the 250 mg dose used previously. However, more research is necessary to clarify these dosing parameters. The adverse effects reported are consistent with the side effects observed previously with other endocrine medications. Thus, the efficacy and safety of fulvestrant are well established.[13] [Level 1]


References

[1] Boér K, Fulvestrant in advanced breast cancer: evidence to date and place in therapy. Therapeutic advances in medical oncology. 2017 Jul;     [PubMed PMID: 28717399]
[2] Lee CI,Goodwin A,Wilcken N, Fulvestrant for hormone-sensitive metastatic breast cancer. The Cochrane database of systematic reviews. 2017 Jan 3;     [PubMed PMID: 28043088]
[3] Markham A, Alpelisib: First Global Approval. Drugs. 2019 Jul;     [PubMed PMID: 31256368]
[4] Slamon DJ,Neven P,Chia S,Fasching PA,De Laurentiis M,Im SA,Petrakova K,Bianchi GV,Esteva FJ,Martín M,Nusch A,Sonke GS,De la Cruz-Merino L,Beck JT,Pivot X,Sondhi M,Wang Y,Chakravartty A,Rodriguez-Lorenc K,Taran T,Jerusalem G, Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. The New England journal of medicine. 2020 Feb 6;     [PubMed PMID: 31826360]
[5] Turner NC,Ro J,André F,Loi S,Verma S,Iwata H,Harbeck N,Loibl S,Huang Bartlett C,Zhang K,Giorgetti C,Randolph S,Koehler M,Cristofanilli M, Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. The New England journal of medicine. 2015 Jul 16;     [PubMed PMID: 26030518]
[6] Nathan MR,Schmid P, A Review of Fulvestrant in Breast Cancer. Oncology and therapy. 2017;     [PubMed PMID: 28680952]
[7] Croxtall JD,McKeage K, Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women. Drugs. 2011 Feb 12;     [PubMed PMID: 21319872]
[8] Bross PF,Cohen MH,Williams GA,Pazdur R, FDA drug approval summaries: fulvestrant. The oncologist. 2002;     [PubMed PMID: 12490735]
[9] Morales-Conde M,López-Ibáñez N,Calvete-Candenas J,Mendonça FMI, Fulvestrant-induced toxic epidermal necrolysis. Anais brasileiros de dermatologia. 2019 Mar-Apr;     [PubMed PMID: 31090829]
[10] Vergote I,Robertson JF, Fulvestrant is an effective and well-tolerated endocrine therapy for postmenopausal women with advanced breast cancer: results from clinical trials. British journal of cancer. 2004 Mar;     [PubMed PMID: 15094759]
[11] Hawle H,Hess D,Mueller A,Thuerlimann B, Low-Dose Fulvestrant Maintained Long-Term Complete Remission after Poor Response to Previous Endocrine Therapies in a Patient with Advanced Breast Cancer. Case reports in oncology. 2010 Apr 29;     [PubMed PMID: 20740185]
[12] Robertson JF,Harrison M, Fulvestrant: pharmacokinetics and pharmacology. British journal of cancer. 2004 Mar;     [PubMed PMID: 15094758]
[13] Chia S,Gradishar W,Mauriac L,Bines J,Amant F,Federico M,Fein L,Romieu G,Buzdar A,Robertson JF,Brufsky A,Possinger K,Rennie P,Sapunar F,Lowe E,Piccart M, Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 Apr 1;     [PubMed PMID: 18316794]