Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients.
OBJECTIVE
To investigate the activity of letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment (PST) in elderly breast cancer patients.


METHODS
One hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to primary letrozole therapy (2.5 mg daily for 6 months) or a combination of letrozole plus oral cyclophosphamide (50 mg/daily for 6 months) in an open-labeled, randomized phase II trial. Tumor response was assessed clinically, and tumor Ki67 index and vascular endothelial growth factor (VEGF) -A levels were measured before and after treatment.


RESULTS
Overall response rate was 71.9% (95% CI, 60.0 to 83.8) in the 57 patients randomly assigned to receive primary letrozole and 87.7% (95% CI, 78.6 to 96.2) in the 57 patients randomly assigned to receive letrozole plus cyclophosphamide. The difference in activity between treatment arms was predominantly confined to patients with ductal histology. There was a significantly greater suppression of Ki67 and VEGF-A expression in the letrozole/cyclophosphamide-treated group than in the letrozole-treated group, leading to lower Ki67 and VEGF expression at post-treatment residual histology (P = .03 and P = .002, respectively).


CONCLUSIONS
Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients. Metronomic scheduling of cyclophosphamide may have an antiangiogenic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial.
Bottini
Alberto
A
Breast Unit and Anatomia Patologica, Azienda Ospedaliera Istituti Ospitalieri Cremona, Italy.
Generali
Daniele
D
Brizzi
Maria Pia
MP
Fox
Stephen B
SB
Bersiga
Alessandra
A
Bonardi
Simone
S
Allevi
Giovanni
G
Aguggini
Sergio
S
Bodini
Giuliana
G
Milani
Manuela
M
Dionisio
Rossana
R
Bernardi
Claudio
C
Montruccoli
Arianna
A
Bruzzi
Paolo
P
Harris
Adrian L
AL
Dogliotti
Luigi
L
Berruti
Alfredo
A
D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D000077289:Letrozole; D008875:Middle Aged; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D020533:Angiogenesis Inhibitors; D018906:Antineoplastic Agents, Alkylating; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D009570:Nitriles; D014230:Triazoles; D042461:Vascular Endothelial Growth Factor A; D000077289:Letrozole; D003520:Cyclophosphamide