Fulvestrant for the treatment of locally advanced ormetastatic breast cancer

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; ALCARAZ, A.; GLUJOVSKY, D.; LOPEZ, A.; REY-ARES, L.; BARDACH, A.; CIAPPONI, A; GONZALEZ, L

Documento de Evaluación de tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Breast cancer is the most common neoplasm and the main cause of cancer death in women. Five to ten percent of breast cancers are at advanced stages at the time of diagnosis, with a 12-month mean overall survival. Seventy percent of them express estrogen receptors (ER), being sequential hormonal therapy administration its main therapeutic strategy. In postmenopausal patients, aromatase inhibitors (anastrozole, letrozole, exemestane) are recommended as first line therapy. The use of fulvestrant is proposed as a therapeutic alternative both as first line and second line therapy.TechnologyFulvestrant is an ER competitive antagonist. It has been approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer, whose disease has relapsed during or after anti-adjuvant therapy with antiestrogens.PurposeTo assess the available evidence on the efficacy, safety and coverage policy related issues regarding the use of fulvestrant in patients with locally advanced or metastatic breast cancer.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCTs); health technology and economic assessments (HTA), clinical practice guidelines (CPG) and coverage policies of other health systems.ResultsTo prepare this document, a systematic review, eight RCTs, three CPGs, two HTAs, four coverage policies and one summary published in a congress were included.Use of fulvestrant as second line hormonal therapyFulvestrant 250mg (F250) versus another hormonal agent.One meta-analysis published in 2009, which included four RCTs (n=2,125) did not find significant differences when comparing overall survival (OS) or progression-free survival (PFS) between F250 and anastrozole, exemestane or tamoxifen (the latter as first line treatment).Another study published in 2011, comparing F250 versus anastrozole in 234 Asian patients, did not find statistically significant differences on PFS.F250 versus F250 at a loading dose versus Fulvestrant 500 mg (F500)Two Phase II RCTs (FINDER 1 and 2 n total=287) did not find significant differences when assessing PFS among the different administration schemes.F250 versus F500.In 2010, the preliminary results of CONFIRM Study were published . This report described an OS of 25.1 months for the F500 group compared with 22.8 months for the F250, with no statistically significant differences. PFS in the F500 group was 6.5 months versus 5.5 months for the F250 (n=374) (HR 0.80; CI95%: 0.68 to 0.94). In 2012, the final results were published in a summary at an International Symposium. The OS reported was 26.4 months for F500 compared to 22.3 months for F250 (HR 0.81; CI95%: 0.69 ? 0.96).Use of fulvestrant as first line hormonal therapyF500 versus Anastrozole.The FIRST Study published in 2012 (n=205) reported a PFS of 23.4 months favoring F500 of 13.1 months for anastrozole (HR 0.66; CI95% 0.47 ? 0.92).Loading F250 dose schedule plus Anastrozole versus Anastrozole.A published RCT in 2012 (n=694) reported a 6.4 months difference in OS favoring the combined therapy group (47.7 vs. 41.3 months; HR: 0.81; CI95% 0.65 to 1.00). PFS was 15 months in the combined treatment group compared with 13.5 months in the anastrozole group (HR: 0.80; CI95% 0.68 ? 0.94).Another published RCT with different characteristics in the study group (n=514) did not find significant differences in OS or PFS between both regimens, 37.8 and 10.8 months in the F250/DC versus 38.2 and 10.2 months in the anastrozole group, respectively.Clinical Practice GuidelinesThe main international societies mention fulvestrant as a second line therapy option.Health Technology AssessmentsIn 2008, the Ontario Cancer Care Center mentions fulvestrant as an option together with anastrozole for postmenopausal women who have relapsed with adjuvant tamoxifen or progressed during its use for metastatic disease. On the contrary, NICE (2011) does not recommend it as a treatment alternative. The preparation of these recommendations was based on the preliminary results of some of the above mentioned studies.CostsIn Argentina, the approximate cost of one dose of F500 is AR$7,100 (Argentine Pesos/February 2013), which is equivalent to US$1,420 (U.S. Dollars/February 2013).Coverage PoliciesFour U.S. health insurance companies cover fulvestrant therapeutic use for the 500 mg month scheme as second line hormonal therapy.ConclusionsThe evidence found is of good methodological quality. It supports the use of fulvestrant as second line hormonal therapy; the 500 mg dose being most widely recommended. When assessing the use of fulvestrant in combination with anastrozole as first line therapy, the results of the RCT found are contradictory; therefore new results are required to enable recommending this regimen.