New aromatase inhibitors as second-line endocrine therapy in postmenopausal patients with metastatic breast carcinoma: a pooled analysis of the randomized trials.
BACKGROUND
New aromatase inhibitors (AI) (second-generation: formestane and fadrozole; third-generation: letrozole, anastrozole, vorozole, and exemestane) have been tested in several controlled clinical trials after tamoxifen failure in metastatic breast carcinoma (MBC). They have resulted in better survival compared with megestrol acetate (MEG) in a number of studies. The authors performed a pooled analysis including all the Phase III trials published between 1996 and 2004 evaluating the AIs approved or not by the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medical Products (EMEA) as second-line endocrine therapy (ET) for patients with MBC.


METHODS
The overall response rate (ORR) and time to disease progression (TTP) were considered the primary end points, whereas toxicity was regarded as a secondary objective. Relative risk, 95% confidence interval, and heterogeneity were derived using 2 methods.


RESULTS
No significant differences in ORR and TTP were noted in the entire group of 9 trials comparing AI with MEG (3908 patients) and in the 6 trials comparing nonsteroidal AI and MEG (2415 patients). AI yielded significantly more hot flashes than MEG (P = 0.004) but caused significantly less toxicity than MEG in weight gain (P = 0.001), dyspnea (P = 0.008), and peripheral edema (P = 0.03). Significant heterogeneity for nausea, weight gain, dyspnea, and peripheral edema was registered. When steroidal AIs were excluded from the toxicity analysis, nausea maintained its strongly significant heterogeneity (P = 0.0002), whereas weight gain, dyspnea, and peripheral edema lost their significance.


CONCLUSIONS
This pooled analysis suggested that AIs in second-line ET for patients with MBC do not seem to add any significant benefit to MEG in terms of ORR and TTP. With regard to toxicity, the findings in the current study showed that weight gain, dyspnea, and peripheral edema are more frequent with the use of MEG, whereas hot flashes were more represented using AI.
Carlini
Paolo
P
Department of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy. pcarlini@iol.it pcarlini@yahoo.it
Bria
Emilio
E
Giannarelli
Diana
D
Ferretti
Gianluigi
G
Felici
Alessandra
A
Papaldo
Paola
P
Fabi
Alessandra
A
Nisticò
Cecilia
C
Di Cosimo
Serena
S
Ruggeri
Enzo Maria
EM
Milella
Michele
M
Mottolese
Marcella
M
Terzoli
Edmondo
E
Cognetti
Francesco
F
D000368:Aged; D000077384:Anastrozole; D000735:Androstenedione / Q000008:administration & dosage / Q000031:analogs & derivatives; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy / Q000401:mortality / Q000556:secondary*; D017326:Clinical Trials, Phase III as Topic; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D017316:Fadrozole / Q000008:administration & dosage; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009367:Neoplasm Staging; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage; D017698:Postmenopause; D011336:Probability; D011379:Prognosis; D012074:Remission Induction; D018570:Risk Assessment; D016019:Survival Analysis; D014230:Triazoles / Q000008:administration & dosage
D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; C060523:vorozole; D000077384:Anastrozole; D000735:Androstenedione; D000077289:Letrozole; D017316:Fadrozole; C014594:formestane