The evidence of equivalent, if not higher, efficacy of fulvestrant (Faslodex) compared to aromatase inhibitors (AIs) as well as tamoxifen is indisputable, and oncology leaders like Bill Gradishar, Robert Livingston, John Robertson, Gabriel Hortobagyi, Adam Brufsky, Gerson Locker, Stephen Jones, and Charles Vogel, and dozens of other leading clinical investigators have concurred, and voiced their opinions eloquently, that it is regrettably a highly effective but severely underutilized endocrine option, with typically superior tolerability in addition, and this has been the conclusion of the systematic review of fulvestrant compared to other endocrine agents conducted last year by Adam Buzdar at MD Anderson, along with innumerable other research studies to the same effect. I'll just quote the conclusions of 2 out of several hundred sources, both published in the peer-reviewed Community Oncology journal's series on fulvestrant published earlier this year:
" . . . fulvestrant likely produces less arthralgia than does letrozole and exemestane . . . Fulvestrant produced less arthralgias than the AIs . . . and fewer estrogenic effects than tamoxifen. . . . Moreover, few women discontinued fulvestrant therapy due to adverse events in the phase III studies . . . Phase III studies also demonstrate fulvestrant's favorable safety and tolerability profile, compared with other hormone therapies for breast cancer. "
[Gradishar WJ. Update on fulvestrant for hormone receptor–positive advanced breast cancer. Commun Oncol 2007;4:220–231]
". . . the unique and somewhat poorly understood endocrine agent fulvestrant (Faslodex) . . . These and other trials should continue to clarify how to best exploit the impressive therapeutic features and activity of this powerful endocrine agent."
[Kaniklidis C. Fulvestrant loading, tumor markers, and ongoing trials. Commun Oncol 2007;4:649-650]
Letrozole (Femara) versus Tamoxifen
As to letrozole (Femara), it needs to be granted that it is also an excellent endocrine agent with well-established efficacy and tolerability. That said, as noted by Bill Gradishar above and myself elsewhere, it is likely – but not guaranteed – to produce somewhat more arthralgia: 20.5% on letrozole compared to 13.5% on tamoxifen, with myalgia (muscle pain) being slightly higher at 7.1% for letrozole and 6.1% for tamoxifen.
Although it's been widely cited that more patients in the letrozole group (12.3%) than in the tamoxifen group (11.1%) discontinued therapy early due to adverse events, I found appreciably more salient the fact that more tamoxifen (11.5%) patients than letrozole patients (7.9%) discontinued treatment due to disease progression.
As reported this year by Alan Coates for the International Breast Cancer Study Group (IBCSG) BIG 1-98 trial, the most reliable data we have to date, patients on tamoxifen experience significantly more thromboembolic events (3.8%), but these occur in only a small number of patients on letrozole (about 2%), and incidence of CVA/TIA (aka, stroke) was low and the same for both agents, at 1.4%.
As to incidence of cardiac events (which includes ischemic heart disease and cardiac failure), these are comparable between letrozole (5.5%) and tamoxifen (5.0%), but cardiac events in general were mild, at predominantly grade 1 and 2. In terms of lipid health, incidence of hypercholesterolemia (generally mild) was 50.6% for letrozole compared to 24.6% for tamoxifen.
As to gynecological and menopausal adverse events, incidence of hot flashes was 32.8% for letrozole compared with 37.4% for tamoxifen, while incidence of vaginal bleeding was 3.8% for letrozole compared to 8.3% for tamoxifen, and night sweating incidence was 14.2% for letrozole compared to 17.0% for tamoxifen.
Finally, in terms of endometrial (uterine) cancer, incidence was low, at between 0.1 to 0.2% for letrozole compared to between 0.3 to 0.5% for tamoxifen; note laso there is some evidence that letrozole can decrease tamoxifen-induced endometrial thickening, as found recently in preliminary results reported by Belgium researchers Leilani Morales and Robert Paridaens
· Patients on tamoxifen experienced significantly more:
thromboembolic events, endometrial pathology, hot flashes, night sweats, and vaginal bleeding.
· Patients on letrozole experienced significantly more:
bone fractures, arthralgia, low-grade cholesterol elevation, and cardiovascular events other than ischemic heart disease and cardiac failure.
§ Note1: the relatively higher incidence of low-grade cholesterol elevation with letrozole may be in large part an artifact of a cholesterol-lowering effect of tamoxifen.
§ Note2: although the overall incidence of cardiac adverse events is not significantly different between the two treatments, there was a trend for higher grade cardiac events on letrozole when compared to tamoxifen.