The Role of Metronomic Chemotherapy in the Treatment of Metastatic Colorectal Cancer Patients

  • Lisa Salvatore
  • Federica Zoratto
  • Fotios Loupakis
  • Alfredo Falcone


Neoangiogenesis is a crucial therapeutic target for metastatic colorectal cancer as demonstrated by the effectiveness of biologic drugs with exclusive or partial antiangiogenic activity such as bevacizumab, aflibercept, and regorafenib. Metronomic chemotherapy may be an alternative strategy for targeting tumor angiogenesis and several clinical studies suggested its promising activity and its extremely favorable toxicity profile in the treatment of metastatic colorectal cancer patients.


mCRC Patient Oral Cyclophosphamide Favorable Toxicity Profile Metronomic Chemotherapy Metastatic Colorectal Cancer Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Ferrara N (2004) Vascular endothelial growth factor as a target for anticancer therapy. Oncologist 9(Suppl 1):2–10PubMedCrossRefGoogle Scholar
  2. 2.
    Saltz LB, Clarke S, Diaz-Rubio E et al (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26:2013–2019PubMedCrossRefGoogle Scholar
  3. 3.
    Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRefGoogle Scholar
  4. 4.
    Kabbinavar F, Hurwitz HI, Fehrenbacher L et al (2003) Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60–65PubMedCrossRefGoogle Scholar
  5. 5.
    Van Cutsem E, Tabernero J, Lakomy R et al (2012) Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30:3499–3506PubMedCrossRefGoogle Scholar
  6. 6.
    Grothey A, Van Cutsem E, Sobrero A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303–312PubMedCrossRefGoogle Scholar
  7. 7.
    Bocci G, Falcone A, Fioravanti A et al (2008) Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib. Br J Cancer 98:1619–1629PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    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 U S A 100:12917–12922PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Bocci G, Nicolaou KC, Kerbel RS (2002) Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res 62:6938–6943PubMedGoogle Scholar
  10. 10.
    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 102:1207–1212PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Ogata Y, Sasatomi T, Akagi Y et al (2009) Dosage escalation study of S-1 and irinotecan in metronomic chemotherapy against advanced colorectal cancer. Kurume Med J 56:1–7PubMedCrossRefGoogle Scholar
  12. 12.
    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
  13. 13.
    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
  14. 14.
    Ogata Y, Tanaka T, Akagi Y et al (2013) Multicenter phase II study of a new effective S-1 and irinotecan combination Schedule in patients with unresectable metastatic or recurrent colorectal cancer. Clin Med Insights Oncol 7:21–30PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    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 98:1312–1319PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    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 15:275–286PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Marmorino F, Cremolini C, Loupakis F, Salvatore L (2013) Metronomic capecitabine (cape) and cyclophosphamide (CTX) for refractory metastatic colorectal cancer (mCRC): results of a phase II trial. J Clin Oncol 31(Suppl): abstr e14577. ASCO 2013 2013Google Scholar
  18. 18.
  19. 19.
    Masi G, Loupakis F, Salvatore L et al (2010) Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol 11:845–852PubMedCrossRefGoogle Scholar
  20. 20.
    Falcone A, Cremolini C, Gianluca M (2013) FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): results of the phase III TRIBE trial by GONO group. J Clin Oncol 31(Suppl): abstr 3505. ASCO 2013 2013Google Scholar
  21. 21.
    Koopman M, Simkens LHJ, Ten Tije AJ (2013) Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): the phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 31(Suppl); abstr 3502. ASCO 2013 2013Google Scholar
  22. 22.
    Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4:423–436PubMedCrossRefGoogle Scholar
  23. 23.
    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
  24. 24.
    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

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Lisa Salvatore
    • 1
  • Federica Zoratto
    • 1
  • Fotios Loupakis
    • 1
  • Alfredo Falcone
    • 1
    • 2
  1. 1.U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano TumoriPisaItaly
  2. 2.Dipartimento di Oncologia dei Trapianti e delle Nuove Tecnologie in MedicinaUniversità di PisaPisaItaly

Personalised recommendations