Metronomic Cyclophosphamide Adds Value to Neoadjuvant Hormonal Therapy for Elderly Breast Cancer Patients

Abstract & Commentary

By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.

Synopsis: In a trial in elderly women with breast cancer, primary systemic (neoadjuvant) therapy with letrozole with or without low dose daily oral cyclophosphamide was shown to increase overall clinical response. Furthermore, at the time of surgical resection, residual breast tumor tissue had reduced Ki67 and VEGF immunostaining in samples from those treated with the combined letrozole-cyclophosphamide regimen, suggesting the added cytotoxic drug may be inhibiting endothelial cell proliferation and angiogenic response.

Source: Bottini A, et al. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol. 2006:24:3623-3628.

Primary systemic therapy (PST) has become increasingly utilized as a method of determining sensitivity of breast cancer to chemotherapy and hormonal manipulation. For example, in hormone receptor positive postmenopausal women, endocrine treatment has been shown to significantly reduce tumor volume prior to surgical resection.1,2 In the current report, the addition of low-dose, oral daily cyclophosphamide to hormonal therapy was tested in elderly women with breast cancer. The trial was conducted at various centers in Italy and included 114 consecutive elderly women with clinically determined T2-4, N0-1, ER positive breast cancer. Patients were enrolled who were older than 70 years of age, or 65-69 years but considered unfit for systemic chemotherapy on the basis of clinical evaluation.

All patients were ECOG performance status 0-2 with adequate marrow reserve, hepatic and renal function. Patients were randomized to letrozole (LET) alone (n = 57) or LET plus cyclophosphamide (LET-CYC) (n = 57). LET was administered at a dose of 2.5 mg/day and CYC at a dose of 50 mg/day.

Of the 114 patients, 104 completed the planned 6 months of therapy (n = 52 in each arm). The overall response rate was 50 of 57 (87.7%; 95% CI, 78.6-96.2) in the LET-CYC arm and 41 of 57 (71.9%; 95% CI, 60.8-83.8) in the LET arm. There were 25 (43.8%) complete clinical responses in the LET-CYC group compared with 23 (40.3%) for those receiving LET alone. Somewhat disappointingly, however, pathologic responses (no evident tumor at the time of surgical excision) were observed in only two patients, one in each treatment arm. Yet, overall the combined treatment was associated with a 2.79 (95% CI, 1.05-7.42) increased odds of response when compared with LET alone (P = 0.04).

Of note, Ki67 expression was measured in 88 matched cases. At baseline, no difference in Ki67 immunostaining was observed and both LET and LET-CYC treatments resulted in a significant reduction in Ki67 expression. At post-chemotherapy assessment, Ki67 expression was lower in samples from the LET-CYC patients. Similarly, vascular endothelial growth factor (VEGF) immunostaining was significantly lower in samples from the LET-CYC patients (P < 0.002). Specifically, 35.5% of patients in the LET-CYC group had their VEGF staining become negative compared to 7.9% in the LET alone group.


Thus, both letrozole and letrozole plus cyclophosphamide treatments were active as primary systemic therapy in elderly patients with breast cancer. The data would suggest that the added low-dose oral cyclophosphamide increases overall and complete clinical response rate and this may be as a result of an antiangiogenic response as indicated by the significant reduction in VEGF immunostaining.

There has been increasing interest in the concept of 'metronomic' chemotherapy (eg, low dose but daily cytotoxic drug administration) as this approach may theoretically target tumor cells by inhibiting endothelial cell proliferation.3,4 Indeed, in this trial, the reduction in VEGF staining by added low-dose cyclophosphamide would seem to support this contention. The enhanced effect may be more than this; however, since Ki67, a marker of tumor cell proliferation, was also reduced by the added cyclophosphamide.

As mentioned, there were disappointingly few pCRs in this trial, not unlike prior experience of hormonal therapy in the neoadjuvant setting.2,5,6 Thus, the overall value of neoadjuvant hormonal therapy with or without added metronomic chemotherapy remains to be determined pending additional relevant clinical outcomes such as disease free, and overall survival.


1. Cleator S, et al. The biology of neoadjuvant chemotherapy for breast cancer. Endocr Relat Cancer. 2002;9:183-195.

2. Eiermann W, et al. Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol. 2001;12:1527-1532.

3. Colleoni M, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002;13:73-80.

4. Rozados VR, et al. Metronomic therapy with cyclophosphamide induces rat lymphoma and sarcoma regression, and is devoid of toxicity. Ann Oncol. 2004;15:1543-1550.

5. Bottini A, et al. Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial. Endocr Relat Cancer. 2005;12:383-392.

6. Colleoni M, et al. Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment. Clin Cancer Res. 2004;10:6622-6628.