Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 1, pp 13–33

Metronomic chemotherapy for cancer treatment: a decade of clinical studies

  • Adriana Romiti
  • M. Christina Cox
  • Ida Sarcina
  • Roberta Di Rocco
  • Chiara D’Antonio
  • Viola Barucca
  • Paolo Marchetti
Review Article

Abstract

Purpose

Over the past few years, more and more new selective molecules directed against specific cellular targets have become available for cancer therapy, leading to impressive improvements. In this evolving scenario, a new way of delivering older cytotoxic drugs has also been developing. Many studies demonstrated that several cytotoxic drugs have antiangiogenic properties if administered frequently and at lower doses compared with standard schedules containing maximal tolerated doses (MTD). Such a new strategy, named metronomic chemotherapy, focuses on a different target: the slowly proliferating tumour endothelial cells. About 10 years ago, metronomic chemotherapy was firstly enunciated and hereafter many clinical experiences were published related to almost any cancer disease. This review analyses available studies dealing with metronomic chemotherapy and its combination with several targeted agents in solid tumours.

Methods

A computerized literature search of MEDLINE was performed using the following search terms: metronomic OR “continuous low dose” AND chemotherapy AND cancer OR solid tumours.

Results

Satisfactory results have been achieved in diverse tumour types, such as breast and prostate cancer or paediatric sarcomas. Moreover, many studies have reported that metronomic chemotherapy determined minimal toxicity compared to MTD chemotherapy. Overall, published series on metronomic schedules are very heterogeneous often reporting on retrospective data, while only very few studies were randomized trials. These limitations still prevent to draw definitive conclusions in diverse tumour types.

Conclusions

Large well-designed studies are eagerly awaited for confirming the promises of metronomic schedules and their combinations with targeted molecules.

Keywords

Metronomic chemotherapy Cancer therapy “Continuous low dose” chemotherapy Solid tumours 

References

  1. 1.
    Krause DS, Van Etten RA (2005) Tyrosine kinases as targets for cancer therapy. N Engl J Med 353:172–187PubMedCrossRefGoogle Scholar
  2. 2.
    Skipper HE, Schabel FM, Wilcox WS (1964) Experimental evaluation of potential anticancer agents. XIII. On the criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemother Rep 35:1–111PubMedGoogle Scholar
  3. 3.
    Gasparini G (2001) Metronomic scheduling: the future of chemotherapy? Lancet Oncol 2:733–740PubMedCrossRefGoogle Scholar
  4. 4.
    Browder T, Butterfield CE, Kräling BM et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 7:1878–1886Google Scholar
  5. 5.
    Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436PubMedCrossRefGoogle Scholar
  6. 6.
    Klement G, Baruchel S, Rak J et al (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumour regression without overt toxicity. J Clin Invest 105:R15–R24PubMedCrossRefGoogle Scholar
  7. 7.
    Hanahan D, Bergers G, Bergsland E (2000) Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumour angiogenesis in mice. J Clin Invest 105:1045–1047PubMedCrossRefGoogle Scholar
  8. 8.
    Kamen BA, Rubin E, Aisner J et al (2000) High-Time chemotherapy or high time for low dose. J Clin Oncol 18:2935–2937PubMedGoogle Scholar
  9. 9.
    Engelsman E, Klijn JC, Rubens RD et al (1991) “Classical” CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. An EORTC breast cancer co-operative group phase III trial (10808). Eur J Cancer 27:966–970PubMedCrossRefGoogle Scholar
  10. 10.
    Kakolyris S, Samonis G, Koukourakis M et al (1998) Treatment of non-small-cell lung cancer with prolonged oral etoposide. Am J Clin Oncol 21:505–508PubMedCrossRefGoogle Scholar
  11. 11.
    Lokich J, Anderson N (1997) Dose intensity for bolus versus infusion chemotherapy administration: review of the literature for 27 anti-neoplastic agents. Ann Oncol 8:15–25PubMedCrossRefGoogle Scholar
  12. 12.
    Seidman AD, Hudis CA, Albanel J et al (1998) Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16:3353–3361PubMedGoogle Scholar
  13. 13.
    Burstein HJ, Manola J, Younger J et al (2000) Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 18:1212–1219PubMedGoogle Scholar
  14. 14.
    Abu-Rustum NR, Aghajanian C, Barakat RR et al (1997) Salvage weekly paclitaxel in recurrent ovarian cancer. Semin Oncol 24:S15-62–S15-67Google Scholar
  15. 15.
    Green MC, Buzdar AU, Smith T et al (2005) Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 week. JCO 23:5983–5992CrossRefGoogle Scholar
  16. 16.
    Sparano JA, Wang M, Martino S et al (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663–1671PubMedCrossRefGoogle Scholar
  17. 17.
    Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose ‘‘chemo-switch’’ regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23:939–952PubMedCrossRefGoogle Scholar
  18. 18.
    Pasquier E, Kavallaris M, André N (2010) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7:455–465PubMedCrossRefGoogle Scholar
  19. 19.
    Miller KD, Sweeney CJ, Sledge GW (2001) Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol 19:1195–1206PubMedGoogle Scholar
  20. 20.
    Lee KA, Qian DZ, Rey S et al (2009) Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci 106:2353–2358PubMedCrossRefGoogle Scholar
  21. 21.
    Kim YJ, Lee HJ, Kim TM et al (2013) Overcoming evasive resistance from vascular endothelial growth factor a inhibition in sarcomas by genetic or pharmacologic targeting of hypoxia-inducible factor 1α. Int J Cancer 132:29–41PubMedCrossRefGoogle Scholar
  22. 22.
    André N, Padovani L, Pasquier E (2011) Metronomic scheduling of anticancer treatments: the next generation of multi target therapy? Future Oncol 7:385–394PubMedCrossRefGoogle Scholar
  23. 23.
    Chuu CP, Hiipakka RA, Fukuchi J et al (2005) Androgen causes growth suppression and reversion of androgen-independent prostate cancer xenografts to an androgen stimulated phenotype in athymic mice. Cancer Res 65:2082–2084PubMedCrossRefGoogle Scholar
  24. 24.
    Choi LM, Rood B, Kamani N et al (2008) Feasibility of metronomic maintenance chemotherapy following high-dose chemotherapy for malignant central nervous system tumors. Pediatr Blood Cancer 50:970–975PubMedCrossRefGoogle Scholar
  25. 25.
    Peyrl A, Chocholous M, Kieran MW et al (2012) Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer 59:511–517PubMedCrossRefGoogle Scholar
  26. 26.
    Scadden DT (2006) The stem-cell niche as an entity of action. Nature 441:1075–1079PubMedCrossRefGoogle Scholar
  27. 27.
    Calabrese C, Poppleton H, Kocak M et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82PubMedCrossRefGoogle Scholar
  28. 28.
    Folkins C, Man S, Xu P et al (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560–3564PubMedCrossRefGoogle Scholar
  29. 29.
    Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996PubMedCrossRefGoogle Scholar
  30. 30.
    Wong ET, Hess KR, Gleason MJ et al (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578PubMedGoogle Scholar
  31. 31.
    Kurzen H, Schmitt S, Naher H et al (2003) Inhibition of angiogenesis by non-toxic doses of temozolomide. Anticancer Drugs 14:515–522PubMedCrossRefGoogle Scholar
  32. 32.
    Tuettenberg J, Grobholz R, Korn T et al (2005) Continuous low-dose chemotherapy plus inhibition of cyclooxygenase-2 as an antiangiogenic therapy of glioblastoma multiforme. J Cancer Res Clin Oncol 131:31–40PubMedCrossRefGoogle Scholar
  33. 33.
    Fulton D, Urtasun R, Forsyth P (1996) Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma. J Neurooncol 27:149–155PubMedCrossRefGoogle Scholar
  34. 34.
    Herrlinger U, Rieger J, Steinbach JP et al (2005) UKT-04 trial of continuous metronomic low-dose chemotherapy with methotrexate and cyclophosphamide for recurrent glioblastoma. J Neurooncol 71:295–299PubMedCrossRefGoogle Scholar
  35. 35.
    Kesari S, Schiff D, Doherty L et al (2007) Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults. Neuro Oncol 9:354–363PubMedCrossRefGoogle Scholar
  36. 36.
    Reardon DA, Desjardins A, Vredenburgh JJ et al (2009) Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study. Br J Cancer 101:1986–1994PubMedCrossRefGoogle Scholar
  37. 37.
    Kong DS, Lee JI, Kim JH et al (2010) Phase II trial of low-dose continuous (metronomic) treatment of temozolomide for recurrent glioblastoma. Neuro Oncol 12:289–296PubMedCrossRefGoogle Scholar
  38. 38.
    Perry JR, Bélanger K, Mason WP et al (2010) Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 28:2051–2057PubMedCrossRefGoogle Scholar
  39. 39.
    Stockhammer F, Misch M, Koch A et al (2010) Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma. J Neurooncol 100:407–415PubMedCrossRefGoogle Scholar
  40. 40.
    Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729PubMedCrossRefGoogle Scholar
  41. 41.
    Reardon DA, Desjardins A, Peters K et al (2011) Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J Neurooncol 103:371–379PubMedCrossRefGoogle Scholar
  42. 42.
    Desjardins A, Reardon DA, Coan A et al (2012) Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 118:1302–1312PubMedCrossRefGoogle Scholar
  43. 43.
    Friedman HS, Prados MD, Wen PY et al (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27:4733–4740PubMedCrossRefGoogle Scholar
  44. 44.
    Clarke JL, Iwamoto FM, Sul J et al (2009) Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. J Clin Oncol 27:3861–3867PubMedCrossRefGoogle Scholar
  45. 45.
    Sterba J, Valik D, Mudry P et al (2006) Combined biodifferentiating and antiangiogenic oral metronomic therapy is feasible and effective in relapsed solid tumors in children: single-center pilot study. Onkologie 29:308–313PubMedCrossRefGoogle Scholar
  46. 46.
    Janss AJ, Minturn JE, Fisher PG et al (2011) A phase II study of metronomic oral topotecan for recurrent childhood brain tumors. Pediatr Blood Cancer 56:39–44PubMedCrossRefGoogle Scholar
  47. 47.
    Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  48. 48.
    Miller K, Wang M, Gralow J et al (2007) Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 357:2666–2676PubMedCrossRefGoogle Scholar
  49. 49.
    Miles DW, Chan A, Dirix LY (2010) Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 28:3239–3247PubMedCrossRefGoogle Scholar
  50. 50.
    Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRefGoogle Scholar
  51. 51.
    Thomas ES, Gomez HL, Li RK et al (2007) Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 25:5210–5217PubMedCrossRefGoogle Scholar
  52. 52.
    Ge Y, Domschke C, Stoiber N et al (2012) Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol Immunother 61:353–362PubMedCrossRefGoogle Scholar
  53. 53.
    Colleoni M, Rocca A, Sandri MTM et al (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumour activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13:73–80PubMedCrossRefGoogle Scholar
  54. 54.
    Miscoria M, Tonetto F, Deroma L et al (2011) Exploratory predictive and prognostic factors in advanced breast cancer treated with metronomic chemotherapy. Anticancer Drugs 23:326–334CrossRefGoogle Scholar
  55. 55.
    Gebbia V, Boussen H, Valerio MR et al (2012) Oral metronomic cyclophosphamide with and without methotrexate as palliative treatment for patients with metastatic breast carcinoma. Anticancer Res 32:529–536PubMedGoogle Scholar
  56. 56.
    Colleoni M, Orlando L, Sanna G et al (2006) Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumour activity and biological effects. Ann Oncol 17:232–238PubMedCrossRefGoogle Scholar
  57. 57.
    Wong NS, Buckman RA, Clemons M et al (2010) 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 response. J Clin Oncol 28:723–730PubMedCrossRefGoogle Scholar
  58. 58.
    Khan OA, Blann AD, Payne MJ et al (2011) Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer. Br J Cancer 104:1822–1827PubMedCrossRefGoogle Scholar
  59. 59.
    Orlando L, Cardillo A, Ghisini R et al (2006) Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer 6:225PubMedCrossRefGoogle Scholar
  60. 60.
    Gonzalez-Billalabeitia E, Calzas J, Castellano D et al (2009) Long-term follow-up of an anthracycline-containing metronomic chemotherapy schedule in advanced breast cancer. Breast J 15:551–553PubMedCrossRefGoogle Scholar
  61. 61.
    Dellapasqua S, Mazza M, Colleoni M et al (2011) Pegylated liposomal doxorubicin in combination with low-dose metronomic cyclophosphamide as preoperative treatment for patients with locally advanced breast cancer. Breast 20:319–323PubMedCrossRefGoogle Scholar
  62. 62.
    Wang Z, Lu J, Leaw S, Hong X et al (2012) An all-oral combination of metronomic cyclophosphamide plus capecitabine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: a phase II study. Cancer Chemother Pharmacol 69:515–522PubMedCrossRefGoogle Scholar
  63. 63.
    Yoshimoto M, Takao S, Hirata M et al (2012) Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer. Cancer Chemother Pharmacol 70:331–338PubMedCrossRefGoogle Scholar
  64. 64.
    Fedele P, Marino A, Orlando L et al (2012) Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer. Eur J Cancer 48:24–29PubMedCrossRefGoogle Scholar
  65. 65.
    Smith IE, Johnston SR, O’Brien ME et al (2000) Low-dose oral fluorouracil with eniluracil as first-line chemotherapy against advanced breast cancer: a phase II study. J Clin Oncol 18:2378–2384PubMedGoogle Scholar
  66. 66.
    Young SD, Lafrenie RM, Clemons MJ (2012) Phase II trial of a metronomic schedule of docetaxel and capecitabine with concurrent celecoxib in patients with prior anthracycline exposure for metastatic breast cancer. Curr Oncol 19:e75–e78PubMedCrossRefGoogle Scholar
  67. 67.
    Addeo R, Sgambato A, Cennamo G et al (2010) Low dose metronomic oral administration of vinorelbine in the first line treatment of elderly patients with metastatic breast cancer. Clinical Breast Cancer 4:301–306CrossRefGoogle Scholar
  68. 68.
    Licchetta A, Correale P, Migali C et al (2010) Oral metronomic chemo-hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate. J Chemother 22:201–204PubMedGoogle Scholar
  69. 69.
    Bottini A, Generali D, Brizzi MP et al (2006) 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 24:3623–3628PubMedCrossRefGoogle Scholar
  70. 70.
    Dellapasqua S, Bertolini F, Bagnardi V et al (2008) Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 26:4899–4905PubMedCrossRefGoogle Scholar
  71. 71.
    Montagna E, Cancello G, Bagnardi V et al (2012) Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity. Clin Breast Cancer 12:207–214PubMedCrossRefGoogle Scholar
  72. 72.
    Garcia-Saenz JA, Martin M, Calles A et al (2008) Bevacizumab in combination with metronomic chemotherapy in patients with anthracycline- and taxane refractory breast cancer. J Chemother 20:632–639PubMedGoogle Scholar
  73. 73.
    Saloustros E, Kalbakis K, Vardakis N et al (2011) Metronomic vinorelbine plus bevacizumab as salvage therapy for patients with metastatic breast cancer. J Buon 16:215–218PubMedGoogle Scholar
  74. 74.
    Soriano JL, Batista N, Santiesteban E et al (2011) Metronomic cyclophosphamide and methotrexate chemotherapy combined with 1E10 anti-idiotype vaccine in metastatic breast cancer. Int J Breast Cancer 2011:710292PubMedGoogle Scholar
  75. 75.
    Watanabe T, Sano M, Takashima S et al (2009) Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: national surgical adjuvant study for breast cancer 01 trial. J Clin Oncol 27:1368–1374PubMedCrossRefGoogle Scholar
  76. 76.
    Ohashi Y, Watanabe T, Sano M et al (2010) Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (NSAS-BC 01 trial and CUBC trial). Breast Cancer Res Treat 119:633–641PubMedCrossRefGoogle Scholar
  77. 77.
    Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551PubMedCrossRefGoogle Scholar
  78. 78.
    Fossella F, Pereira JR, von Pawel J et al (2003) Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol 21:3016–3024PubMedCrossRefGoogle Scholar
  79. 79.
    Pirker R, Pereira JR, Szczesna A et al (2009) FLEX study TeamCetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 373:1525–1531PubMedCrossRefGoogle Scholar
  80. 80.
    Jackman DM, Miller VA, Cioffredi LA et al (2009) Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumour registry of clinical trials. Clin Cancer Res 15:5267–5273PubMedCrossRefGoogle Scholar
  81. 81.
    Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al (2005) National Cancer Institute of Canada Clinical Trials GroupErlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132PubMedCrossRefGoogle Scholar
  82. 82.
    Kato H, Ichinose Y, Ohta M et al (2004) A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350:1713–1721PubMedCrossRefGoogle Scholar
  83. 83.
    Correale P, Cerretani D, Remondo C et al (2006) A novel metronomic chemotherapy regimen of weekly platinum and daily oral etoposide in high-risk non small cell lung cancer patients. Oncol Rep 16:133–140PubMedGoogle Scholar
  84. 84.
    Correale P, Remondo C, Carbone SF et al (2010) Dose/dense metronomic chemotherapy with fractioned cisplatin and oral daily etoposide enhances the anti-angiogenic effects of bevacizumab and has strong antitumour activity in advanced non-small-cell-lung cancer patients. Cancer Biol Ther 9:685–693PubMedCrossRefGoogle Scholar
  85. 85.
    Correale P, Botta C, Basile A et al (2011) Phase II trial of Bevacizumab and dose/dense chemotherapy with Cisplatin and metronomic daily oral etoposide in advanced non small cell lung cancer patients. Cancer Biol Ther 12:112–118PubMedCrossRefGoogle Scholar
  86. 86.
    Gorn M, Habermann CR, Anige M et al (2008) A pilot study of docetaxel and trofosfamide as second-line ‘metronomic’ chemotherapy in the treatment of metastatic non-small cell lung cancer (NSCLC). Onkologie 31:185–189PubMedGoogle Scholar
  87. 87.
    Tas F, Duranyildiz D, Soydinc HO et al (2008) 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. Cancer Chemother Pharmacol 61:721–725PubMedCrossRefGoogle Scholar
  88. 88.
    Pallis AG, Chandrinos V, Pavlakou G et al (2011) A multicenter phase I trial of metronomic oral vinorelbine plus cisplatin in patients with NSCLC. Cancer Chemother Pharmacol 67:1239–1245PubMedCrossRefGoogle Scholar
  89. 89.
    Kouroussis C, Vamvakas L, Vardakis N et al (2009) Continuous administration of daily low-dose temozolomide in pretreated patients with advanced non-small cell lung cancer: a phase II study. Oncology 76:112–117PubMedCrossRefGoogle Scholar
  90. 90.
    Chen YM, Fan WC, Tsai CM et al (2011) A phase II randomized trial of Gefitinib alone or with tegafur/uracil treatment in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. J Thorac Oncol 6:1110–1116PubMedCrossRefGoogle Scholar
  91. 91.
    Maki RG, Wathen JK, Patel SR et al (2007) Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected]. J Clin Oncol 25:2755–2763 (Erratum in: J Clin Oncol 25:3790)Google Scholar
  92. 92.
    Garcia del Muro X, Lopez-Pousa A, Martin J et al (2005) A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer 104:1706–1712PubMedCrossRefGoogle Scholar
  93. 93.
    van der Graaf WT, Blay JY, Chawla SP et al (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879–1886PubMedCrossRefGoogle Scholar
  94. 94.
    Hartmann JT, Oechsle K, Mayer F et al (2003) Phase II trial of trofosfamide in patients with advanced pretreated soft tissue sarcomas. Anticancer Res 23:1899–1901PubMedGoogle Scholar
  95. 95.
    Vogt T, Hafner C, Bross K et al (2003) Antiangiogenetic therapy with pioglitazone, rofecoxib and metronomic trofosfamide in patients with advanced malignant vascular tumours. Cancer 98:2251–2256PubMedCrossRefGoogle Scholar
  96. 96.
    Reichle A, Bross K, Vogt T et al (2004) Pioglitazone and Rofecoxib combined with angiostatically scheduled trofosfamide in the treatment of far-advanced melanoma and soft tissue sarcoma. Cancer 101:2247–2256PubMedCrossRefGoogle Scholar
  97. 97.
    Briasoulis E, Pappas P, Puozzo C et al (2009) Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer. Clin Cancer Res 15:6454–6461PubMedCrossRefGoogle Scholar
  98. 98.
    Italiano A, Toulmonde M, Lortal B et al (2010) Metronomic chemotherapy in advanced soft tissue sarcomas. Cancer Chemother Pharmacol 66:197–202PubMedCrossRefGoogle Scholar
  99. 99.
    Mir O, Domont J, Cioffi A et al (2011) Feasibility of metronomic oral cyclophosphamide plus prednisolone in elderly patients with inoperabile or metastatic soft tissue sarcoma. Eur J Cancer 47:515–519PubMedCrossRefGoogle Scholar
  100. 100.
    Casanova M, Ferrari A, Bisogno G et al (2004) Vinorelbin and low dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for upcoming European Rhabdomyosarcoma Protocol. Cancer 101:1664–1671PubMedCrossRefGoogle Scholar
  101. 101.
    Minard-Colin V, Ichante JL, Nguyen L et al (2012) Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: good tolerance profile and efficacy in rhabdomyosarcoma–a report from the Société Française des Cancers et leucémies de l’Enfant et de l’adolescent (SFCE). Eur J Cancer 48:2409–2416PubMedCrossRefGoogle Scholar
  102. 102.
    Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723PubMedCrossRefGoogle Scholar
  103. 103.
    Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526PubMedCrossRefGoogle Scholar
  104. 104.
    Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516PubMedCrossRefGoogle Scholar
  105. 105.
    Borne E, Desmedt E, Duhamel A et al (2010) Oral metronomic cyclophosphamide in elderly with metastatic melanoma. Invest New Drugs 28:684–689PubMedCrossRefGoogle Scholar
  106. 106.
    Spieth K, Kaufmann R, Gille J (2003) Metronomic oral low-dose treosulfan chemotherapy combined with cyclooxygenase-2 inhibitor in pretreated advanced melanoma: a pilot study. Cancer Chemother Pharmacol 52:377–382PubMedCrossRefGoogle Scholar
  107. 107.
    Hwu WJ, Krown SE, Menell JH et al (2003) Phase II study of temozolomide plus thalidomide for the treatment of metastatic melanoma. J Clin Oncol 21:3351–3356PubMedCrossRefGoogle Scholar
  108. 108.
    Clark JI, Moon J, Hutchins LF et al (2010) Phase 2 trial of combination thalidomide plus temozolomide in patients with metastatic malignant melanoma: Southwest Oncology Group S0508. Cancer 116:424–431PubMedCrossRefGoogle Scholar
  109. 109.
    Bhatt RS, Merchan J, Parker R et al (2010) A phase 2 pilot trial of low-dose, continuous infusion, or “metronomic” paclitaxel and oral celecoxib in patients with metastatic melanoma. Cancer 116:1751–1756PubMedCrossRefGoogle Scholar
  110. 110.
    Reichle A, Vogt T, Coras B et al (2007) Targeted combined anti-inflammatory and angiostatic therapy in advanced melanoma: a randomized phase II trial. Melanoma Res 17:360–364PubMedCrossRefGoogle Scholar
  111. 111.
    Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390PubMedCrossRefGoogle Scholar
  112. 112.
    Hsu CH, Shen YC, Lin ZZ et al (2010) Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma. J Hepatol 53:126–131PubMedCrossRefGoogle Scholar
  113. 113.
    Shao YY, Lin ZZ, Hsu C et al (2012) Efficacy, safety, and potential biomarkers of thalidomide plus metronomic chemotherapy for advanced hepatocellular carcinoma. Oncology 82:59–66PubMedCrossRefGoogle Scholar
  114. 114.
    Treiber G, Wex T, Malfertheiner P (2009) Impact of different anticancer regimens on biomarkers of angiogenesis in patients with advanced hepatocellular cancer. Cancer Res Clin Oncol 135:271–281CrossRefGoogle Scholar
  115. 115.
    Van Cutsem E, Köhne CH, Láng I et al (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumour KRAS and BRAF mutation status. J Clin Oncol 29:2011–2019PubMedCrossRefGoogle Scholar
  116. 116.
    Jonker DJ, O’Callaghan CJ, Karapetis CS et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048PubMedCrossRefGoogle Scholar
  117. 117.
    Allegrini G, Falcone A, Fioravanti A et al (2008) A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients. Br J Cancer 98:1312–1319PubMedCrossRefGoogle Scholar
  118. 118.
    Steinbild S, Arends J, Medinger M et al (2007) Metronomic antiangiogenic therapy with capecitabine and celecoxib in advanced tumour patients–results of a phase II study. Onkologie 30:629–635PubMedCrossRefGoogle Scholar
  119. 119.
    Young SD, Whissell M, Noble JC et al (2006) Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumours. Clin Cancer Res 12:3092–3098PubMedCrossRefGoogle Scholar
  120. 120.
    Allegrini G, Di Desidero T, Barletta MT et al (2012) Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers. Angiogenesis 15:275–286PubMedCrossRefGoogle Scholar
  121. 121.
    Ogata Y, Sasatomi T, Mori S et al (2007) Significance of thymidine phosphorylase in metronomic chemotherapy using CPT-11 and doxifluridine for advanced colorectal carcinoma. Anticancer Res 27:2605–2611PubMedGoogle Scholar
  122. 122.
    Lin PC, Chen WS, Chao TC et al (2007) Biweekly oxaliplatin plus 1-day infusional fluorouracil/leucovorin followed by metronomic chemotherapy with tegafur/uracil in pretreated metastatic colorectal cancer. Cancer Chemother Pharmacol 60:351–356PubMedCrossRefGoogle Scholar
  123. 123.
    Ogata Y, Mori S, Ishibashi N et al (2007) Metronomic chemotherapy using weekly low-dosage CPT-11 and UFT as postoperative adjuvant therapy in colorectal cancer at high risk to recurrence. J Exp Clin Cancer Res 26:475–482PubMedGoogle Scholar
  124. 124.
    Pyrhönen S, Kuitunen T, Nyandoto P et al (1995) Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 71:587–591PubMedCrossRefGoogle Scholar
  125. 125.
    Wu H, Xin Y, Zhao J et al (2011) Metronomic docetaxel chemotherapy inhibits angiogenesis and tumour growth in a gastric cancer model. Cancer Chemother Pharmacol 68:879–887PubMedCrossRefGoogle Scholar
  126. 126.
    Cejka D, Preusser M, Woehrer A et al (2008) Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biol Ther 7:1377–1385PubMedCrossRefGoogle Scholar
  127. 127.
    He S, Shen J, Hong L, Niu L (2011) Capecitabine “metronomic” chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy. Med Oncol 9:100–106Google Scholar
  128. 128.
    Brizzi MP, Berruti A, Ferrero A et al (2009) Continuous 5-fluorouracil infusion plus long acting octreotide in advanced well-differentiated neuroendocrine carcinomas. A phase II trial of the Piemonte oncology network. BMC Cancer 9:388PubMedCrossRefGoogle Scholar
  129. 129.
    Petrylak DP, Tangen CM, Hussain MH et al (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513–1520PubMedCrossRefGoogle Scholar
  130. 130.
    Berthold DR, Pond GR, Soban F et al (2008) Docetaxel plus prednisone or Mitoxantrone plus prednisoefor advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 26:242–245PubMedCrossRefGoogle Scholar
  131. 131.
    de Bono JS, Oudard S, Ozguroglu M et al (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376:1147–1154PubMedCrossRefGoogle Scholar
  132. 132.
    de Bono JS, Logothetis CJ, Molina A et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995–2005PubMedCrossRefGoogle Scholar
  133. 133.
    Lord R, Nair S, Schache A et al (2007) Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study. J Urol 177:2136–2140PubMedCrossRefGoogle Scholar
  134. 134.
    Glode LM, Barqawi A, Crighton F et al (2003) Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer 98:1643–1648PubMedCrossRefGoogle Scholar
  135. 135.
    Nelius T, Klatte T, De Reise W et al (2010) Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy. Med Oncol 27:363–367PubMedCrossRefGoogle Scholar
  136. 136.
    Ladoire S, Eymard JC, Zanetta S et al (2010) Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure. Anticancer Res 30:4317–4323PubMedGoogle Scholar
  137. 137.
    Fontana A, Galli L, Fioravanti A et al (2009) Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res 15:4954–4962PubMedCrossRefGoogle Scholar
  138. 138.
    Nishimura K, Nonomura N, Ono Y et al (2001) Oral combination of cyclophosphamide, uracil plus tegafur and estramustine for hormone-refractory prostate cancer. Oncology 60:49–54PubMedCrossRefGoogle Scholar
  139. 139.
    Gebbia V, Serretta V, Borsellino N et al (2011) Salvage therapy with oral metronomic cyclophosphamide and methotrexate for castration-refractory metastatic adenocarcinoma of the prostate resistant to docetaxel. Urology 78:1125–1130PubMedCrossRefGoogle Scholar
  140. 140.
    Hatano K, Nonomura N, Nishimura K et al (2011) Retrospective analysis of an oral combination of dexamethasone, uracil plus tegafur and cyclophosphamide for hormone-refractory prostate cancer. Jpn J Clin Oncol 41:253–259PubMedCrossRefGoogle Scholar
  141. 141.
    Nelius T, Rinard K, Filleur S (2011) Oral/metronomic cyclophosphamide-based chemotherapy as option for patients with castration-refractory prostate cancer—review of the literature. Cancer Treat Rev 37:444–455PubMedCrossRefGoogle Scholar
  142. 142.
    Motzer RJ, Hutson TE, Tomczak P et al (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124PubMedCrossRefGoogle Scholar
  143. 143.
    Sternberg CN, Davis ID, Mardiak J et al (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068PubMedCrossRefGoogle Scholar
  144. 144.
    Escudier B, Eisen T, Stadler WM et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134PubMedCrossRefGoogle Scholar
  145. 145.
    Motzer RJ, Escudier B, Oudard S et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456PubMedCrossRefGoogle Scholar
  146. 146.
    Rini BI, Escudier B, Tomczak P et al (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378:1931–1939PubMedCrossRefGoogle Scholar
  147. 147.
    Eisen T, Boshoff C, Mak I et al (2000) Continuous low dose thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer. Br J Cancer 82:812–817PubMedCrossRefGoogle Scholar
  148. 148.
    Krzyzanowska MK, Tannock IF, Lockwood G et al (2007) A phase II trial of continuous low-dose oral cyclophosphamide and celecoxib in patients with renal cell carcinoma. Cancer Chemother Pharmacol 60:135–141PubMedCrossRefGoogle Scholar
  149. 149.
    Walter B, Schrettenbrunner I, Vogelhuber M et al (2011) Pioglitazone, etoricoxib, interferon-α, and metronomic capecitabine for metastatic renal cell carcinoma: final results of a prospective phase II trial. Med Oncol 29:799–805PubMedCrossRefGoogle Scholar
  150. 150.
    Bellmunt J, Trigo JM, Calvo E et al (2010) Activity of a multitargeted chemo-switch regimen (sorafenib, gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02-06). Lancet Oncol 11:350–357PubMedCrossRefGoogle Scholar
  151. 151.
    Burger RA, Brady MF, Bookman MA et al (2011) Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473–2483PubMedCrossRefGoogle Scholar
  152. 152.
    Naumann RW, Coleman RL (2011) Management strategies for recurrent platinum-resistant ovarian cancer. Drugs 71:1397–1412PubMedCrossRefGoogle Scholar
  153. 153.
    Chura JC, Van Iseghem K, Downs LS et al (2007) Bevacizumab plus cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. Gynecol Oncol 107:326–330PubMedCrossRefGoogle Scholar
  154. 154.
    Sanchez-Munoz A, Mendiola C, Perez-Ruiz E et al (2010) Bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. Oncology 79:98–100PubMedCrossRefGoogle Scholar
  155. 155.
    Garcia AA, Hirte H, Fleming G et al (2008) 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 26:76–82PubMedCrossRefGoogle Scholar
  156. 156.
    Collovà E et al (2011) Use of metronomic chemotherapy in oncology: results from a national Italian survey. Tumori 97:454–458PubMedGoogle Scholar
  157. 157.
    Shaked Y, Emmenegger U, Man S et al (2005) Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106:3058–3061PubMedCrossRefGoogle Scholar
  158. 158.
    Ghiringhelli F, Menard C, Puig PE et al (2007) Metronomic cyclophosphamide regimen selectively depletesCD4 + CD25 + regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56:641–648PubMedCrossRefGoogle Scholar
  159. 159.
    Banissi C, Ghiringhelli F, Chen L, Carpentier AF (2009) Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother 58:1627–1634PubMedCrossRefGoogle Scholar
  160. 160.
    Generali D, Bates G, Berruti A et al (2009) Immunomodulation of FOXP3 + regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients. Clin Cancer Res 15:1046–1051PubMedCrossRefGoogle Scholar
  161. 161.
    Streubel B, Chott A, Huber D et al (2004) Lymphoma-specific genetic aberrations in microvascular endothelial cells in B-cell lymphomas. N Engl J Med 351:250–259PubMedCrossRefGoogle Scholar
  162. 162.
    Rigolin GM, Fraulini C, Ciccone M et al (2006) Neoplastic circulating endothelial cells in multiple myeloma with 13q14 deletion. Blood 107:2531–2535PubMedCrossRefGoogle Scholar
  163. 163.
    Akiyama K, Ohga N, Hida Y et al (2012) Tumor endothelial cells acquire drug resistance by MDR1 up-regulation via VEGF signaling in tumor microenvironment. Am J Pathol 180:1283–1293PubMedCrossRefGoogle Scholar
  164. 164.
    Pasquier E, Tuset MP, Street J et al (2012) Concentration- and schedule-dependent effects of chemotherapy on the angiogenic potential and drug sensitivity of vascular endothelial cells. Angiogenesis (Epub ahead of print)Google Scholar
  165. 165.
    Bertolini F, Paul S, Mancuso P et al (2003) Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63:4342–4346PubMedGoogle Scholar
  166. 166.
    Francia G, Shaked Y, Hashimoto K et al (2012) Low-dose metronomic oral dosing of a prodrug of gemcitabine (LY2334737) causes antitumour effects in the absence of inhibition of systemic vasculogenesis. Mol Cancer Ther 11:680–689PubMedCrossRefGoogle Scholar
  167. 167.
    Wu L, Tannock I (2003) Repopulation in murine breast tumours during and after sequential treatments with cyclophosphamide and 5-fluorouracil. Cancer Res 63:2134–2138PubMedGoogle Scholar
  168. 168.
    Noberasco C, Spitaleri G, Mancuso P et al (2009) Safety, tolerability and biological effects of long-term metronomic administration of non-cytotoxic anti-angiogenic agents. Oncology 77:358–365PubMedCrossRefGoogle Scholar
  169. 169.
    Shao YY, Lin ZZ, Chen TJ et al (2011) High circulating endothelial progenitor levels associated with poor survival of advanced hepatocellular carcinoma patients receiving sorafenib combined with metronomic chemotherapy. Oncology 81:98–103PubMedCrossRefGoogle Scholar
  170. 170.
    Bertolini F, Marighetti P, Shaked Y (2010) Cellular and soluble markers of tumor angiogenesis: from patient selection to the identification of the most appropriate postresistance therapy. Biochim Biophys Acta 1806:131–137PubMedGoogle Scholar
  171. 171.
    Calleri A, Bono A, Bagnardi V et al (2009) Predictive potential of angiogenic growth factors and circulating endothelial cells in breast cancer patients receiving metronomic chemotherapy plus bevacizumab. Clin Cancer Res 15:7652–7657PubMedCrossRefGoogle Scholar
  172. 172.
    Twardowski PW, Smith-Powell L, Carroll M et al (2008) Biologic markers of angiogenesis: circulating endothelial cells in patients with advanced malignancies treated on phase I protocol with metronomic chemotherapy and celecoxib. Cancer Invest 26:53–59PubMedCrossRefGoogle Scholar
  173. 173.
    Bocci G, Francia G, Man S et al (2003) Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA 100:12917–12922PubMedCrossRefGoogle Scholar
  174. 174.
    Kieran MW, Turner CD, Rubin JB et al (2005) Feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol 27:573–581PubMedCrossRefGoogle Scholar
  175. 175.
    Lansiaux A, Salingue S, Dewitte A et al (2012) Circulating thrombospondin 1 level as a surrogate marker in patients receiving cyclophosphamide-based metronomic chemotherapy. Invest New Drugs 30:403–404PubMedCrossRefGoogle Scholar
  176. 176.
    Penel N, Clisant S, Dansin E et al (2010) Megestrol acetate versus metronomic cyclophosphamide in patients having exhausted all effective therapies under standard care. Br J Cancer 102:1207–1212PubMedCrossRefGoogle Scholar
  177. 177.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedCrossRefGoogle Scholar
  178. 178.
    Cabral FR (1983) Isolation of Chinese hamster ovary cell mutants requiring the continuous presence of taxol for cell division. J Cell Biol 97:22–29PubMedCrossRefGoogle Scholar
  179. 179.
    Kavallaris M, Kuo DY, Burkhart CA et al (1997) Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J Clin Invest 100:1282–1293PubMedCrossRefGoogle Scholar
  180. 180.
    Yang CP, Verdier-Pinard P, Wang F et al (2005) A highly epothilone B-resistant A549 cell line with mutations in tubulin that confer drug dependence. Mol Cancer Ther 4:987–995PubMedCrossRefGoogle Scholar
  181. 181.
    Zapletalova D, Andre N, Deak L et al (2012) Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: a multicenter experience. Oncology 82:249–260PubMedCrossRefGoogle Scholar
  182. 182.
    Bocci G, Nicolaou KC, Kerbel RS (2002) Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a elective antiangiogenic window for various chemotherapeutic drugs. Cancer Res 62:6938–6943PubMedGoogle Scholar
  183. 183.
    Le Deley MC, Leblanc T, Shamsaldin A et al (2003) Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case–control study by the Société Française d’Oncologie Pédiatrique. J Clin Oncol 21:1074–1081PubMedCrossRefGoogle Scholar
  184. 184.
    Shaikh AJ, Masood N (2010) Acute lymphoblastic leukemia subsequent to temozolomide use in a 26-year-old man: a case report. J Med Case Reports 4:274CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Adriana Romiti
    • 1
  • M. Christina Cox
    • 2
  • Ida Sarcina
    • 1
  • Roberta Di Rocco
    • 1
  • Chiara D’Antonio
    • 1
  • Viola Barucca
    • 1
  • Paolo Marchetti
    • 1
  1. 1.Department of Oncology, Faculty of Medicine and PsychologySapienza University, Sant’Andrea HospitalRomeItaly
  2. 2.Department of Hematology, Faculty of Medicine and PsychologySapienza University, Sant’Andrea HospitalRomeItaly

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