The Indian Journal of Pediatrics

, Volume 79, Issue 12, pp 1617–1622 | Cite as

Metronomic Chemotherapy in Progressive Pediatric Malignancies: Old Drugs in New Package

Special Article

Abstract

Despite intensive research in the field of cancer, many pediatric cancers are still incurable with current treatment protocols. Repetitive administration of conventional chemotherapy at maximal tolerated dose imposes many side effects that further limits the dosing and therefore decreases the anticancer effects. Usually limited options remain when a malignancy progresses after one or two lines of standard chemotherapy protocol. The goal of an oncologist at this point of time remains mainly palliative with an effort to halt the progression of cancer and improve quality of life. Metronomic chemotherapy is defined as the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks. It is thought this type of chemotherapy inhibits tumor growth primarily through anti-angiogenic mechanisms, promoting apoptosis and immune- surveillance.

Keywords

Metronomic chemotherapy Drugs Pediatric malignancy 

References

  1. 1.
    Steen RG. What is cancer? In Steen RG, Mirro J, eds. Childhood cancer: A handbook from St. Jude Children’s Research Hospital, Perseus Publishing Cambridge; 2000. pp. 3–10.Google Scholar
  2. 2.
    Canadian Cancer Society, National Cancer Institute of Canada, Statistics Canada, Provincial/Terretorial Cancer Registries, and Health Canada. Canadian Cancer Statistics 2004.Google Scholar
  3. 3.
    Canadian Cancer Statistics 2000. Cancer in Children aged 0–19 yrs. National Cancer Institute of Canada: Cancer Statistics 2000, Toronto, Canada, 2000. Accessed June 22nd, 2005. Online: http://www.cancer.ca/stats2000.childe.htm
  4. 4.
    Shimizu K, Oku N. Cancer anti-angiogenic therapy. Biol Pharm Bull. 2004;27:599–605.PubMedCrossRefGoogle Scholar
  5. 5.
    Fidler IJ, Ellis LM. Chemotherapeutic drugs: more really is not better. Nat Med. 2000;6:500–2.PubMedCrossRefGoogle Scholar
  6. 6.
    Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays. 1991;13:31–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Kerbel RS. A cancer therapy resistant to resistance. Nature. 1997;390:335–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Gasparini G. The rationale and future potential of angiogenesis inhibitors in neoplasia. Drugs. 1999;58:17–38.PubMedCrossRefGoogle Scholar
  10. 10.
    Fox SB, Gasparini G, Harris AL. Angiogenesis: pathological, prognostic, and growth-factor pathways and their link to trial design and anticancer drugs. Lancet Oncol. 2001;2:278–89.PubMedCrossRefGoogle Scholar
  11. 11.
    Miller KD, Sweeney CJ, Sledge Jr GW. Redefining the target: chemotherapeutics as antiangiogenics. J Clin Oncol. 2001;19:1195–206.PubMedGoogle Scholar
  12. 12.
    Eberhard A, Kahlert S, Goede V, Hemmerlein B, Plate KH, Augustin HG. Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res. 2000;60:1388–93.PubMedGoogle Scholar
  13. 13.
    Klement G, Baruchel S, Rak J, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 2000;105:R15–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Browder T, Butterfield CE, Kräling, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drugresistant cancer. Cancer Res. 2000;60:1878–86.PubMedGoogle Scholar
  15. 15.
    Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423–36.PubMedCrossRefGoogle Scholar
  16. 16.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Kosmaczewska A, Ciszak L, Potoczek S, Frydecka I. The significance of Treg cells in defective tumor immunity. Arch Immunol Ther Exp (Warsz). 2008;56:181–91.CrossRefGoogle Scholar
  18. 18.
    Kono K, Kawaida H, Takahashi A, et al. CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother. 2006;55:1064–71.PubMedCrossRefGoogle Scholar
  19. 19.
    Ghiringhelli F, Larmonier N, Schmitt E, et al. CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol. 2004;34:336–44.PubMedCrossRefGoogle Scholar
  20. 20.
    Loeffler M, Krüger JA, Reisfeld RA. Immunostimulatory effects of low-dose cyclophosphamide are controlled by inducible nitric oxide synthase. Cancer Res. 2005;65:5027–30.PubMedCrossRefGoogle Scholar
  21. 21.
    Lutsiak ME, Semnani RT, De Pascalis R, Kashmiri SV, Schlom J, Sabzevari H. Inhibition of CD4 (+) 25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood. 2005;105:2862–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Matsushima H, Takashima A. Cyclophosphamide, DCs, and Tregs. Blood. 2010;115:4322–4.PubMedCrossRefGoogle Scholar
  23. 23.
    Tanaka H, Matsushima H, Mizumoto N, Takashima A. Classification of chemotherapeutic agents based on their differential in vitro effects on dendritic cells. Cancer Res. 2009;69:6978–86.PubMedCrossRefGoogle Scholar
  24. 24.
    Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401–10.PubMedCrossRefGoogle Scholar
  25. 25.
    Audia S, Nicolas A, Cathelin D, et al. Increase of CD4+ CD25+ regulatory T cells in the peripheral blood of patients with metastatic carcinoma:A phase I clinical trial using cyclophosphamide and immunotherapy to eliminate CD4+ CD25+T lymphocytes. Clin Exp Immunol. 2007;150:523–30.PubMedCrossRefGoogle Scholar
  26. 26.
    Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell. 1998;93:705–16.PubMedCrossRefGoogle Scholar
  27. 27.
    Masferrer JL, Leahy KM, Koki AT, et al. Antiangiogenic and antitumour activities of cyclooxygenase-2 inhibitors. Cancer Res. 2000;60:1306–11.PubMedGoogle Scholar
  28. 28.
    Gupta RA, Dubois RN. Combinations for cancer prevention. Nat Med. 2000;6:974–5.PubMedCrossRefGoogle Scholar
  29. 29.
    Hsueh CT, Chiu CF, Kelsen DP, Schwartz GK. Selective inhibition of cyclooxygenase-2 enhances mitomycin-C-induced apoptosis. Cancer Chemother Pharmacol. 2000;45:389–96.PubMedCrossRefGoogle Scholar
  30. 30.
    D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA. 1994;91:4082–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Yoneda T, Alsina MA, Chavez JB, Bonewald L, Nishimura R, Mundy GR. Evidence that tumour necrosis factor plays a pathogenetic role in the paraneoplastic syndromes of cachexia, hypercalcaemia, and leukocytosis in a human tumour in nude mice. J Clin Invest. 1991;87:977–85.PubMedCrossRefGoogle Scholar
  32. 32.
    Cabral FR. Isolation of Chinese hamster ovary cell mutants requiring the continuous presence of taxol for cell division. J Cell Biol. 1983;97:22–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Wong NS, Buckman RA, Clemons M, 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 response. J Clin Oncol. 2010;28:723–30.PubMedCrossRefGoogle Scholar
  34. 34.
    Garcia AA, Hirte H, Fleming G, 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. 2008;26:76–82.PubMedCrossRefGoogle Scholar
  35. 35.
    Sarmiento R, Gasparini G. Antiangiogenic metronomic chemotherapy. Onkologie. 2008;31:161–2.PubMedCrossRefGoogle Scholar
  36. 36.
    Patil V, Noronha V, D’cruz AK, Banavali SD, Prabhash K. Metronomic chemotherapy in advanced oral cancers. J Cancer Res Ther. 2012;8:S106–10.PubMedCrossRefGoogle Scholar
  37. 37.
    Sterba J, Pavelka Z, Slampa P. Concomitant radiotherapy and metronomic temozolomide in pediatric high-risk brain tumors. Neoplasma. 2002;49:117–20.PubMedGoogle Scholar
  38. 38.
    Kieran MW, Turner CD, Rubin JB, et al. A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol. 2005;27:573–81.PubMedCrossRefGoogle Scholar
  39. 39.
    Fousseyni T, Diawana M, Pasquier E, André N. Children treated with metronomic chemotherapy in a low-income country: METRO-MALI-01. J Pediatr Hematol Oncol. 2011;33:31–4.PubMedCrossRefGoogle Scholar
  40. 40.
    Stempak D, Gammon J, Halton J, Moghrabi A, Koren G, Baruchel SA. pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors. J Pediatr Hematol Oncol. 2006;28:720–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Choi LM, Rood B, Kamani N, et al. Feasibility of metronomic maintenance chemotherapy following high-dose chemotherapy for malignant central nervous system tumors. Pediatr Blood Cancer. 2008;50:970–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Minturn JE, Janss AJ, Fisher PG, et al. A phase II study of metronomic oral topotecan for recurrent childhood brain tumors. Pediatr Blood Cancer. 2011;56:39–44.PubMedCrossRefGoogle Scholar
  43. 43.
    Bocci G, Tuccori M, Emmenegger U, et al. Cyclophosphamide methotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol. 2005;16:1243–52.PubMedCrossRefGoogle Scholar
  44. 44.
    De Vita S, De Matteis S, Laurenti L, et al. Secondary Ph+ acute lymphoblastic leukemia after temozolomide. Ann Hematol. 2005;84:760–2.PubMedCrossRefGoogle Scholar
  45. 45.
    Rome A, André N, Scavarda D, et al. Metronomic chemotherapy induced bilateral subdural hematoma in a child with meningeal carcinomatosis. Pediatr Blood Cancer. 2009;53:246–7.PubMedCrossRefGoogle Scholar

Copyright information

© Dr. K C Chaudhuri Foundation 2012

Authors and Affiliations

  1. 1.Department of Medical Oncology, Dr. B. R. A. Institute Rotary Cancer HospitalAll India Institute of Medical SciencesNew DelhiIndia

Personalised recommendations