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Randomized Phase II Trial of Letrozole and Letrozole Plus Low-Dose Metronomic Oral Cyclophosphamide As Primary Systemic Treatment in Elderly Breast Cancer Patients

Alberto Bottini, Daniele Generali, Maria Pia Brizzi, Stephen B. Fox, Alessandra Bersiga, Simone Bonardi, Giovanni Allevi, Sergio Aguggini, Giuliana Bodini, Manuela Milani, Rossana Dionisio, Claudio Bernardi, Arianna Montruccoli, Paolo Bruzzi, Adrian L. Harris, Luigi Dogliotti, Alfredo Berruti

From the Breast Unit and Anatomia Patologica, Azienda Ospedaliera Istituti Ospitalieri Cremona; Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Azienda Ospedaliera San Luigi, Orbassano; Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; and the John Radcliffe Hospital Oxford, United Kingdom

Address reprint requests to Luigi Dogliotti MD, Oncologia Medica, Azienda Ospedaliera San Luigi, Regione Gondole 10, 10043 Orbassano, Italy; e-mail: luigi.dogliotti{at}unito.it

PURPOSE: To investigate the activity of letrozole plus/minus oral metronomic cyclophophamide 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).

CONCLUSION: Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients. Metronomic scheduling of cyclophosphamide may have an antiangiogenetic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial.

Supported in part by the Associazione Patologia Oncologica Mammaria –APOM, Cremona, Italy; the association of Amici dell’ospedale di Cremona; a grant from the Consiglio Nazionale Ricerche, Rome, Italy; Cancer Research UK; and the European Union via the Euroxy Grant.

A.Bo. and D.G. contributed equally to study design and conduct and manuscript preparation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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