Low-dose metronomic chemotherapy: from past experience to new paradigms in the treatment of cancer.

Low-dose metronomic (LDM) chemotherapy represents an emerging concept in the treatment of cancer. Directed against tumor cells and other types of cells, such as endothelial and immune cells, this treatment regimen alters the tumor microenvironment and suppresses innate features which support tumor growth. Ongoing Phase III clinical studies explore various applications of LDM chemotherapy, mostly combined with other anticancer agents, to act as complementary treatments to conventional maximum tolerated dose (MTD) chemotherapy. In this article we summarize preclinical and clinical experience with LDM chemotherapy, emphasizing the potential contribution of this new treatment modality to future paradigms in the systemic treatment of patients with cancer.

[1]  G. Klement,et al.  Nontoxic, fiscally responsible, future of oncology: could it be beginning in the Third World? , 2011, Journal of pediatric hematology/oncology.

[2]  J. Whang‐Peng,et al.  A Phase II Randomized Trial of Gefitinib Alone or with Tegafur/Uracil Treatment in Patients with Pulmonary Adenocarcinoma Who had Failed Previous Chemotherapy , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[3]  R. Kerbel,et al.  Potent Preclinical Impact of Metronomic Low-Dose Oral Topotecan Combined with the Antiangiogenic Drug Pazopanib for the Treatment of Ovarian Cancer , 2009, Molecular Cancer Therapeutics.

[4]  R. Kerbel,et al.  Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  D. Waxman,et al.  VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. , 2012, Cancer research.

[6]  R. Kerbel,et al.  Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. , 2008, Cancer cell.

[7]  G. Brandi,et al.  Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers , 2012, Angiogenesis.

[8]  A. Berruti,et al.  Metronomic Therapy Concepts in the Management of Adrenocortical Carcinoma , 2011, Hormones & cancer.

[9]  M. Hashizume,et al.  Combination with low-dose gemcitabine and hTERT-promoter-dependent conditionally replicative adenovirus enhances cytotoxicity through their crosstalk mechanisms in pancreatic cancer. , 2010, Cancer letters.

[10]  H. Wakimoto,et al.  Enhanced Antitumor Efficacy of Low-Dose Etoposide with Oncolytic Herpes Simplex Virus in Human Glioblastoma Stem Cell Xenografts , 2011, Clinical Cancer Research.

[11]  G. Botti,et al.  Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. , 2010, Clinical breast cancer.

[12]  Jie Shen,et al.  Capecitabine “metronomic” chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy , 2012, Medical Oncology.

[13]  A. Goldhirsch,et al.  Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer , 2006, BMC Cancer.

[14]  D. Thamm,et al.  Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma. , 2011, Journal of veterinary internal medicine.

[15]  E. Voest,et al.  Chemotherapy enhances metastasis formation via VEGFR-1-expressing endothelial cells. , 2011, Cancer research.

[16]  C. Tinelli,et al.  UFT as Maintenance Therapy in Patients with Advanced Colorectal Cancer Responsive to the FOLFOX4 Regimen , 2008, Oncology.

[17]  J. Folkman,et al.  Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. , 2000, Cancer research.

[18]  J. Christensen,et al.  Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy , 2007, Proceedings of the National Academy of Sciences.

[19]  Robert S. Kerbel,et al.  The anti-angiogenic basis of metronomic chemotherapy , 2004, Nature Reviews Cancer.

[20]  R. Burger.  Experience with bevacizumab in the management of epithelial ovarian cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  G. Shurin,et al.  Chemomodulation of human dendritic cell function by antineoplastic agents in low noncytotoxic concentrations , 2009, Journal of Translational Medicine.

[22]  Jin-song Lu,et al.  An all-oral combination of metronomic cyclophosphamide plus capecitabine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: a phase II study , 2012, Cancer Chemotherapy and Pharmacology.

[23]  K. Shirouzu,et al.  Metronomic chemotherapy using weekly low-dosage CPT-11 and UFT as postoperative adjuvant therapy in colorectal cancer at high risk to recurrence. , 2007, Journal of experimental & clinical cancer research : CR.

[24]  P. Carmeliet,et al.  A vascular niche and a VEGF–Nrp1 loop regulate the initiation and stemness of skin tumours , 2011, Nature.

[25]  H. Iwata,et al.  Clinical usefulness of oral combination chemotherapy of 5′;-deoxy-5-fluorouridine (5′;-DFUR) and cyclophosphamide for metastatic Breast Cancer , 2006, Breast Cancer.

[26]  R. Kerbel,et al.  Tumors that acquire resistance to low-dose metronomic cyclophosphamide retain sensitivity to maximum tolerated dose cyclophosphamide. , 2011, Neoplasia.

[27]  M. Valerio,et al.  Salvage therapy with oral metronomic cyclophosphamide and methotrexate for castration-refractory metastatic adenocarcinoma of the prostate resistant to docetaxel. , 2011, Urology.

[28]  R. Kerbel,et al.  Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. , 2003, Cancer research.

[29]  F. Ghiringhelli,et al.  Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model , 2009, Cancer Immunology, Immunotherapy.

[30]  I. Lavi,et al.  Daily low-dose/continuous capecitabine combined with neo-adjuvant irradiation reduces VEGF and PDGF-BB levels in rectal carcinoma patients , 2008, Acta oncologica.

[31]  Zang Ai-hua,et al.  Stem Cells,Cancer and Cancer Stem Cells , 2005 .

[32]  Gabriele Bergers,et al.  Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. , 2000, The Journal of clinical investigation.

[33]  A. Harris,et al.  Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents. , 2009, Cancer research.

[34]  R. Kerbel,et al.  Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. , 2005, Blood.

[35]  A. Goldhirsch,et al.  Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  A. Luini,et al.  Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity. , 2012, Clinical breast cancer.

[37]  T. Ishikawa.  Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma. , 2008, World journal of gastroenterology.

[38]  T. Voloshin,et al.  Host response to short-term, single-agent chemotherapy induces matrix metalloproteinase-9 expression and accelerates metastasis in mice. , 2011, Cancer research.

[39]  A. Koch,et al.  Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma , 2010, Journal of Neuro-Oncology.

[40]  F. Bertolini,et al.  Residual dormant cancer stem-cell foci are responsible for tumor relapse after antiangiogenic metronomic therapy in hepatocellular carcinoma xenografts , 2012, Laboratory Investigation.

[41]  A. Attarbaschi,et al.  Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: results of the randomized ALCL99-vinblastine trial. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  R. Kerbel,et al.  Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. , 2005, Cancer research.

[43]  R. Kerbel,et al.  Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. , 2002, Cancer research.

[44]  R. Kerbel,et al.  Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models , 2009, Molecular Cancer Therapeutics.

[45]  S. Pestka,et al.  Chemotherapeutics and Radiation Stimulate MHC Class I Expression through Elevated Interferon-beta Signaling in Breast Cancer Cells , 2012, PloS one.

[46]  A. Goldhirsch,et al.  Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[47]  F. Tas,et al.  Effect of maximum-tolerated doses and low-dose metronomic chemotherapy on serum vascular endothelial growth factor and thrombospondin-1 levels in patients with advanced nonsmall cell lung cancer , 2008, Cancer Chemotherapy and Pharmacology.

[48]  Myriam Alcalay,et al.  Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells , 2009, Nature.

[49]  Amanda J. Thomas,et al.  A Feasibility Trial of Antiangiogenic (Metronomic) Chemotherapy in Pediatric Patients With Recurrent or Progressive Cancer , 2005, Journal of pediatric hematology/oncology.

[50]  A. Schneeweiss,et al.  Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome , 2012, Cancer Immunology, Immunotherapy.

[51]  John M.L. Ebos,et al.  Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of respon , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  S. Baruchel,et al.  Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. , 2000, The Journal of clinical investigation.

[53]  G. De Velasco,et al.  Bevacizumab plus Low-Dose Metronomic Oral Cyclophosphamide in Heavily Pretreated Patients with Recurrent Ovarian Cancer , 2010, Oncology.

[54]  A. Maraveyas,et al.  From total empiricism to a rational design of metronomic chemotherapy phase I dosing trials , 2006, Anti-cancer drugs.

[55]  A. Sood,et al.  Bridging the Gap between Cytotoxic and Biologic Therapy with Metronomic Topotecan and Pazopanib in Ovarian Cancer , 2010, Molecular Cancer Therapeutics.

[56]  D. Hicklin,et al.  Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. , 2007, Cancer research.

[57]  G. Wahl,et al.  Stem cells, cancer, and cancer stem cells , 2012 .

[58]  R. Figlin,et al.  Evolving role of novel targeted agents in renal cell carcinoma. , 2007, Oncology.

[59]  I. Bayazitov,et al.  A perivascular niche for brain tumor stem cells. , 2007, Cancer cell.

[60]  A. Goldhirsch,et al.  Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[61]  M. Coffey,et al.  Cyclophosphamide Facilitates Antitumor Efficacy against Subcutaneous Tumors following Intravenous Delivery of Reovirus , 2008, Clinical Cancer Research.

[62]  M. Valerio,et al.  Oral metronomic cyclophosphamide with and without methotrexate as palliative treatment for patients with metastatic breast carcinoma. , 2012, Anticancer research.

[63]  L. Landi,et al.  Clinical and Pharmacodynamic Evaluation of Metronomic Cyclophosphamide, Celecoxib, and Dexamethasone in Advanced Hormone-refractory Prostate Cancer , 2009, Clinical Cancer Research.

[64]  Nicolas André,et al.  Metronomic chemotherapy: new rationale for new directions , 2010, Nature Reviews Clinical Oncology.

[65]  N. André,et al.  Pilot study of a pediatric metronomic 4-drug regimen , 2011, Oncotarget.

[66]  I. McNeish,et al.  Low-dose paclitaxel synergizes with oncolytic adenoviruses via mitotic slippage and apoptosis in ovarian cancer , 2010, Oncogene.

[67]  Kristian Pietras,et al.  A multitargeted, metronomic, and maximum-tolerated dose "chemo-switch" regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  S. Fox,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. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[69]  O. Scharovsky,et al.  The immune response and the therapeutic effect of metronomic chemotherapy with cyclophosphamide. , 2009, Oncology research.

[70]  A. Nacci,et al.  Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer. , 2012, European journal of cancer.

[71]  S. Groshen,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. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  F. Ghiringhelli,et al.  Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure. , 2010, Anticancer research.

[73]  T. Nelius,et al.  Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer: review of the literature. , 2011, Cancer treatment reviews.

[74]  N. André,et al.  Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment , 2011, Oncotarget.