Annals of Oncology 13:73-80, 2002
© 2002 European Society for Medical Oncology
Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels
1Division of Medical Oncology, 2Division of Laboratory Medicine and Pathology, 3Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
Received 29 March 2001; revised 26 June 2001; accepted 5 July 2001.
Background
Anticancer chemotherapy is thought to be effective by means of direct cytotoxicity on tumor cells. Alternative mechanisms of efficacy have been ascribed to several common anticancer agents, including cyclophosphamide (CTX), methotrexate (MTX), anthracyclines and taxanes, postulating an antiangiogenic activity.
Patients and methods
We evaluated the clinical efficacy and impact on serum vascular endothelial growth factor (VEGF) levels of low-dose oral MTX and CTX in patients with metastatic breast cancer. MTX was administered 2.5 mg bd on days 1 and 2 each week and CTX 50 mg/day administered continuously.
Results
Sixty-four patients were enrolled, 63 were evaluable: Eastern Cooperative Oncology Group (ECOG) performance status 0–1, 
2 sites of metastatic disease (n = 50 patients), progressive disease at study entry (n = 51), 1 regimen for metastatic disease (n = 32) and 2 regimens (n = 20). Among the 63 evaluable patients, there were two complete remissions (CR), 10 partial remissions (PR) for an overall response rate of 19.0% (95% CI 10.2% to 30.9%) and an overall clinical benefit (CR+ PR+ stable disease >24 weeks) of 31.7% (95% CI 20.6% to 44.7%). Grade 2 leucopenia was registered in only 13 patients. The median serum VEGF level for the subgroup of patients on treatment for at least 2 months decreased with treatment from 315 pg/ml (95% CI 245 to 435) at baseline to 248 pg/ml (95% CI 205 to 311) at 2 months (P <0.001). Both responders and non-responders showed similar reductions in serum VEGF (P = 0.78). After 6 months patients still on treatment had a median VEGF level of 195 pg/ml (95% CI 96 to 355), which was significantly lower than the median baseline values (P = 0.001).
Conclusions
Continuously low-dose CTX and MTX is minimally toxic and effective in heavily pretreated breast cancer patients. A drop in VEGF was associated with the treatment and so alternative hypotheses, other than that of direct toxicity on tumor cells, must be favored when trying to explain the anticancer effect.
Key words: angiogenesis, breast cancer, chemotherapy, cyclophosphamide, methotrexate
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Beslija, J. Bonneterre, H. J. Burstein, V. Cocquyt, M. Gnant, V. Heinemann, J. Jassem, W. J. Kostler, M. Krainer, S. Menard, et al. Third consensus on medical treatment of metastatic breast cancer Ann. Onc., November 1, 2009; 20(11): 1771 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Francia, S. Man, C.-J. Lee, C. R. Lee, P. Xu, M. E. Mossoba, U. Emmenegger, J. A. Medin, and R. S. Kerbel Comparative Impact of Trastuzumab and Cyclophosphamide on HER-2-Positive Human Breast Cancer Xenografts Clin. Cancer Res., October 15, 2009; 15(20): 6358 - 6366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. K. Linderholm, H. Hellborg, U. Johansson, G. Elmberger, L. Skoog, J. Lehtio, and R. Lewensohn Significantly higher levels of vascular endothelial growth factor (VEGF) and shorter survival times for patients with primary operable triple-negative breast cancer Ann. Onc., October 1, 2009; 20(10): 1639 - 1646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Fontana, L. Galli, A. Fioravanti, P. Orlandi, C. Galli, L. Landi, S. Bursi, G. Allegrini, E. Fontana, R. Di Marsico, et al. Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer Clin. Cancer Res., August 1, 2009; 15(15): 4954 - 4962. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dellapasqua, F. Bertolini, V. Bagnardi, E. Campagnoli, E. Scarano, R. Torrisi, Y. Shaked, P. Mancuso, A. Goldhirsch, A. Rocca, et al. Metronomic Cyclophosphamide and Capecitabine Combined With Bevacizumab in Advanced Breast Cancer J. Clin. Oncol., October 20, 2008; 26(30): 4899 - 4905. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Steeg, C. E. Horak, and K. D. Miller Clinical-Translational Approaches to the Nm23-H1 Metastasis Suppressor Clin. Cancer Res., August 15, 2008; 14(16): 5006 - 5012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Holmes, J. C. Huang, T. R. Pace, A. B. Howard, and H. B. Muss Tamoxifen and Aromatase Inhibitors Differentially Affect Vascular Endothelial Growth Factor and Endostatin Levels in Women with Breast Cancer Clin. Cancer Res., May 15, 2008; 14(10): 3070 - 3076. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Laquente, C. Lacasa, M. M. Ginesta, O. Casanovas, A. Figueras, M. Galan, I. G. Ribas, J. R. Germa, G. Capella, and F. Vinals Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model Mol. Cancer Ther., March 1, 2008; 7(3): 638 - 647. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Findlay, G. von Minckwitz, and A. Wardley Effective oral chemotherapy for breast cancer: pillars of strength Ann. Onc., February 1, 2008; 19(2): 212 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Garcia, H. Hirte, G. Fleming, D. Yang, D. D. Tsao-Wei, L. Roman, S. Groshen, S. Swenson, F. Markland, D. Gandara, et al. Phase II Clinical Trial of Bevacizumab and Low-Dose Metronomic Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia J. Clin. Oncol., January 1, 2008; 26(1): 76 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Caballero, J. J. Grau, J. L. Blanch, J. Domingo-Domenech, J. M. Auge, W. Jimenez, and M. Bernal-Sprekelsen Serum Vascular Endothelial Growth Factor as a Predictive Factor in Metronomic (Weekly) Paclitaxel Treatment for Advanced Head and Neck Cancer Arch Otolaryngol Head Neck Surg, November 1, 2007; 133(11): 1143 - 1148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Buckstein, R. S. Kerbel, Y. Shaked, R. Nayar, C. Foden, R. Turner, C. R. Lee, D. Taylor, L. Zhang, S. Man, et al. High-Dose Celecoxib and Metronomic "Low-dose" Cyclophosphamide Is an Effective and Safe Therapy in Patients with Relapsed and Refractory Aggressive Histology Non-Hodgkin's Lymphoma Clin. Cancer Res., September 1, 2006; 12(17): 5190 - 5198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bottini, D. Generali, M. P. Brizzi, S. B. Fox, A. Bersiga, S. Bonardi, G. Allevi, S. Aguggini, G. Bodini, M. Milani, 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., August 1, 2006; 24(22): 3623 - 3628. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. McCarty and K. I. Block Toward a Core Nutraceutical Program for Cancer Management Integr Cancer Ther, June 1, 2006; 5(2): 150 - 171. [Abstract] [PDF]
|
|
|
|
 |
|
 R. S. Kerbel Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science, May 26, 2006; 312(5777): 1171 - 1175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Young, M. Whissell, J. C.S. Noble, P. O. Cano, P. G. Lopez, and C. J. Germond Phase II Clinical Trial Results Involving Treatment with Low-Dose Daily Oral Cyclophosphamide, Weekly Vinblastine, and Rofecoxib in Patients with Advanced Solid Tumors. Clin. Cancer Res., May 15, 2006; 12(10): 3092 - 3098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Bocci, G. Francia, S. Man, J. Lawler, and R. S. Kerbel Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy PNAS, October 28, 2003; 100(22): 12917 - 12922. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Bocci, K. C. Nicolaou, and R. S. Kerbel Protracted Low-Dose Effects on Human Endothelial Cell Proliferation and Survival in Vitro Reveal a Selective Antiangiogenic Window for Various Chemotherapeutic Drugs Cancer Res., December 1, 2002; 62(23): 6938 - 6943. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Salgado, I. Benoy, E. van Marck, P. Vermeulen, and L. Dirix The importance of the VEGF-load in platelets in cancer patients Ann. Onc., October 1, 2002; 13(10): 1689 - 1690. [Full Text] [PDF]
|
|
|
|
|
|
S. Man, G. Bocci, G. Francia, S. K. Green, S. Jothy, D. Hanahan, P. Bohlen, D. J. Hicklin, G. Bergers, and R. S. Kerbel Antitumor Effects in Mice of Low-dose (Metronomic) Cyclophosphamide Administered Continuously through the Drinking Water Cancer Res., May 1, 2002; 62(10): 2731 - 2735. [Abstract] [Full Text] [PDF]
|
|