Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels.

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, > or =2 sites of metastatic disease (n = 50 patients), progressive disease at study entry (n = 51), 1 regimen for metastatic disease (n = 32) and > or =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 > or =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.

[1]  R Bicknell,et al.  Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. , 2000, Cancer research.

[2]  R. Henriksson,et al.  Correlation of vascular endothelial growth factor content with recurrences, survival, and first relapse site in primary node-positive breast carcinoma after adjuvant treatment. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  G. Gastl,et al.  Platelets and VEGF blood levels in cancer patients , 1999, British Journal of Cancer.

[4]  C. Coltman,et al.  The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen level , 1999, British Journal of Cancer.

[5]  D. Hanahan,et al.  Effects of angiogenesis inhibitors on multistage carcinogenesis in mice. , 1999, Science.

[6]  R. Salgado,et al.  Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients , 1999, British Journal of Cancer.

[7]  H. Joensuu,et al.  Leukocytes and platelets of patients with cancer contain high levels of vascular endothelial growth factor. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[8]  S. Campbell,et al.  Serum vascular endothelial growth factor (VEGF) in the normal menstrual cycle: association with changes in ovarian and uterine Doppler blood flow , 1999, Clinical endocrinology.

[9]  I. Hyodo,et al.  Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer. , 1998, European journal of cancer.

[10]  J. Folkman,et al.  Involvement of platelets in tumour angiogenesis? , 1998, The Lancet.

[11]  P. Drew,et al.  Vascular endothelial growth factor in premenopausal women--indicator of the best time for breast cancer surgery? , 1998, British Journal of Cancer.

[12]  G. Hortobagyi,et al.  Treatment of breast cancer. , 1998, The New England journal of medicine.

[13]  Y. Tomita,et al.  Presence of Mucosal Change in the Urinary Bladder in Nonhematuric Patients with Long-Term Exposure and/or Accumulating High-Dose Cyclophosphamide , 1998, Urologia Internationalis.

[14]  D. Tu,et al.  Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  P. Vermeulen,et al.  Vascular endothelial cell growth factor (VEGF) serum concentrations change according to the phase of the menstrual cycle. , 1998, European journal of cancer.

[16]  M. Ratain,et al.  Oral chemotherapy: rationale and future directions. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  H. Verheul,et al.  Platelet: transporter of vascular endothelial growth factor. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  K. Alitalo,et al.  Serum vascular endothelial growth factor is often elevated in disseminated cancer. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[19]  J. Folkman.  New perspectives in clinical oncology from angiogenesis research. , 1996, European journal of cancer.

[20]  A. Harris,et al.  Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. , 1996, Cancer research.

[21]  F. Kern,et al.  The role of angiogenic growth factors in breast cancer progression , 1996, Cancer and Metastasis Reviews.

[22]  G. Sledge.  Implications of the new biology for therapy in breast cancer. , 1996, Seminars in oncology.

[23]  A. Wilks,et al.  Inhibition of growth of C6 glioma cells in vivo by expression of antisense vascular endothelial growth factor sequence. , 1996, Cancer research.

[24]  Brygida Berse,et al.  Vascular permeability factor (VPF, VEGF) in tumor biology , 1993, Cancer and Metastasis Reviews.

[25]  R N Hoover,et al.  Risk of leukemia after chemotherapy and radiation treatment for breast cancer. , 1992, The New England journal of medicine.

[26]  R. Saura,et al.  Inhibition of in vitro vascular endothelial cell proliferation and in vivo neovascularization by low-dose methotrexate. , 1989, Arthritis and rheumatism.

[27]  G. Canellos.  The dose dilemma. , 1988, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  R. Gelman,et al.  Dose-response in the treatment of breast cancer: a critical review. , 1988, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  D. V. Von Hoff,et al.  Use of in vitro dose response effects to select antineoplastics for high-dose or regional administration regimens. , 1986, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  L. Schnipper,et al.  Clinical implications of tumor-cell heterogeneity. , 1986, The New England journal of medicine.

[31]  W. Hryniuk,et al.  The importance of dose intensity in chemotherapy of metastatic breast cancer. , 1984, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  F. Schabel,et al.  Increasing the therapeutic response rates to anticancer drugs by applying the basic principles of pharmacology , 1984, Pharmacology & therapeutics.

[33]  C. Redmond,et al.  The methodologic dilemma in retrospectively correlating the amount of chemotherapy received in adjuvant therapy protocols with disease-free survival. , 1983, Cancer treatment reports.

[34]  W. Louis,et al.  Comparison of intravenous and oral high-dose methotrexate in treatment of solid tumours. , 1979, British medical journal.

[35]  S. Tolchin,et al.  Mechanisms of immunosuppression: effect of cyclophosphamide on responses to influenza immunization. , 1974, The Journal of laboratory and clinical medicine.

[36]  A. Winkelstein,et al.  Mechanisms of immunosuppression: effects of cyclophosphamide on lymphocytes. , 1972, The Journal of laboratory and clinical medicine.

[37]  J. Folkman.  The influence of angiogenesis research on management of patients with breast cancer , 2004, Breast Cancer Research and Treatment.

[38]  M. Toi,et al.  Tumor angiogenesis in breast cancer: Its importance as a prognostic indicator and the association with vascular endothelial growth factor expression , 2004, Breast Cancer Research and Treatment.

[39]  Napoleone Ferrara,et al.  The role of vascular endothelial growth factor in pathological angiogenesis , 2004, Breast Cancer Research and Treatment.

[40]  S. Parangi,et al.  Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. , 1997, Cancer research.

[41]  N. Weidner,et al.  Angiogenesis in breast cancer. , 1996, Cancer treatment and research.

[42]  R. Steiner.  Angiostatic activity of anticancer agents in the chick embryo chorioallantoic membrane (CHE-CAM) assay. , 1992, EXS.

[43]  T. Wagner,et al.  Pharmacokinetics and bioavailability of cyclophosphamide from oral formulations. , 1984, Arzneimittel-Forschung.

[44]  G. Bonadonna,et al.  Dose-response effect of adjuvant chemotherapy in breast cancer. , 1981, The New England journal of medicine.

[45]  Hill Rp,et al.  Pulmonary metastases of the lewis lung tumor-cell kinetics and response to cyclophosphamide at different sizes. , 1977 .