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

Abstract

A B S T R A C T PurposeTo investigate the activity of letrozole plus/minus oral metronomic cyclophophamide as primary systemic treatment (PST) in elderly breast cancer patients. MethodsOne hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptorpositive 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. ResultsOverall 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 ϭ .03 and P ϭ .002, respectively). ConclusionBoth 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.

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

“…In this regard, it is perhaps reassuring that a preclinical study undertaken by Pietras and Hanahan (16) showed outstanding antitumor activity of a combination of daily oral LDM CPA and sunitinib for the treatment of latestage, large islet cell pancreatic carcinoma. Similarly, the combination of letrozole and LDM CPA was both beneficial and devoid of severe or unexpected side effects in the neoadjuvant treatment of breast cancer in elderly patients (13). It also is reassuring that the liver activity of ALDH, the major enzyme involved in the detoxification of CPA and many other compounds and implicated in the resistance to CPA given in a conventional way (23), is not affected by LDM CPA.…”

“…Compared with MTD chemotherapy combined with antiangiogenic compounds, LDM regimens have the potential benefit that they might be combined for more extended periods with targeted antiangiogenic agents, such as antivascular endothelial growth factor receptor-2 antibodies (15) or sunitinib (16), due to the limited toxicity of both types of drugs. Recently, a randomized phase II trial evaluating LDM CPA in combination with the aromatase inhibitor letrozole for the neoadjuvant treatment of breast cancer in elderly patients not only showed excellent tolerance but also enhanced clinical efficacy when LDM CPA was added to letrozole (13).…”

A multicenter phase I trial of metronomic oral vinorelbine plus cisplatin in patients with NSCLC

“…Indeed, several clinical studies have provided evidence supporting the feasibility and activity of the metronomic treatment [8,23,24]. Since antimitotics are thought to be the most appropriate drugs for metronomic use [25,26], vinorelbine is an ideal candidate for metronomic therapy; in addition, vinorelbine is available in oral formulation, which is very convenient for chronic metronomic administration.…”

Therapeutic Usefulness of Postoperative Adjuvant Chemotherapy with Tegafur–Uracil (UFT) in Patients with Breast Cancer: Focus on the Results of Clinical Studies in Japan

“…The mechanism of action was reported to independently involve ER-␣, but to depend on the presence of androstenedione. Clinically, the results of phase II randomized controlled studies comparing letrozole monotherapy with a combination of letrozole and cyclophosphamide as preoperative treatment in women with ER ϩ breast cancer have been reported [38]. Combined therapy resulted in a higher response rate.…”