Development and evolution of the concept of metronomic chemotherapy: A personal perspective

Metronomic Chemotherapy: Pharmacology and Clinical Applications

Volumn , Issue , 2014, Pages 3-21

  Kerbel, Robert S ^a  

^a UNIVERSITY OF TORONTO   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84930447318     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1007/978-3-662-43604-2_1     Document Type: Chapter

References (85)

1. Hanahan D, Bergers G, Bergsland E (2000) Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105:1045-1047
2. Browder T, Butterfield CE, Kraling BM, Marshall B, O'Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drugresistant cancer. Cancer Res 60:1878-1886
3. Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin D, Bohlen P, Kerbel RS (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15-R24
4. Koopman M, Simkens LHJ, Ten Tije AJ, Creemers G-J, Loosveld OJL, de Jongh FE, Erdkamp F, Erjavee Z, van der Torren AME, van der Hoeven JJM, Nieboer P, Braun JJ, Jansen RL, Haasjes JG, Cats A, Wals JJ, Mol L, Dalesio O, van Tinteren H, Punt CJA (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:Abstr 3502
5. Kerbel RS (1991) Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays 13:31-36
6. Rini BI, Atkins MB (2009) Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol 10:992-1000
7. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592-603
8. Yu JL, Rak JW, Coomber BL, Hicklin DJ, Kerbel RS (2002) Effect of p53 status on tumor response to antiangiogenic therapy. Science 295:1526-1528
9. Kerbel RS, Yu J, Tran J, Man S, Viloria-Petit A, Klement G, Coomber BL, Rak J (2001) Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches. Cancer Metastasis Rev 20:79-86
10. Kerbel RS, Viloria-Petit A, Klement G, Rak J (2000) 'Accidental' anti-angiogenic drugs. antioncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. Eur J Cancer 36:1248-1257
11. Klement G, Huang P, Mayer B, Green SK, Man S, Bohlen P, Hicklin D, Kerbel RS (2002) Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR- 2 antibody in multidrug resistant human breast cancer xenograft. Clin Cancer Res 8:221-232
12. Hahnfeldt P, Hlatky L, Klement GL (2013) Center of cancer systems biology second annual workshop-tumor metronomics: timing and dose level dynamics. Cancer Res 73:2949-2954
13. Mayer EL, Isakoff SJ, Klement G, Downing SR, Chen WY, Hannagan K, Gelman R, Winer EP, Burstein HJ (2012) Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics. Breast Cancer Res Treat 136:169-178
14. Kumar S, Bayat Mokhtari R, Sheikh R, Wu B, Zhang L, Xu P, Man S, Dias Oliveira I, Yeger H, Kerbel RS, Baruchel S (2011) Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Clin Cancer Res 17:5656-5667
15. Kelley RK, Hwang J, Magbanua MJ, Watt L, Beumer JH, Christner SM, Baruchel S, Wu B, Fong L, Yeh BM, Moore AP, Ko AH, Korn WM, Rajpal S, Park JW, Tempero MA, Venook AP, Bergsland EK (2013) A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer. Br J Cancer 109:1725-1734
16. Kumar S, Mokhtari RB, Oliveira ID, Islam S, Toledo SR, Yeger H, Baruchel S (2013) Tumor dynamics in response to antiangiogenic therapy with oral metronomic topotecan and pazopanib in neuroblastoma xenografts. Transl Oncol 6:493-503
17. Pasquier E, Kieran MW, Sterba J, Shaked Y, Baruchel S, Oberlin O, Kivivuori MS, Peyrl A, Diawarra M, Casanova M, Zacharoulis S, Vassal G, Berthold F, Verschuur A, Andre N (2011) Moving forward with metronomic chemotherapy: meeting report of the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology. Transl Oncol 4:203-211
18. Mitchell MS (1989) Relapse in the central nervous system in melanoma patients successfully treated with biomodulators. J Clin Oncol 7:1701-1709
19. Mokyr MB, Dray S (1983) Some advantages of curing mice bearing a large subcutaneous MOPC-315 tumor with a low dose rather than a high dose of cyclophosphamide. Cancer Res 43:3112-3119
20. Berd D, Maguire HC Jr, Mastrangelo MJ (1984) Potentiation of human cell-mediated and humoral immunity by low-dose cyclophosphamide. Cancer Res 44:5439-5443
21. Berd D, Mastrangelo MJ (1987) Effect of low dose cyclophosphamide on the immune system of cancer patients: reduction of T-suppressor function without depletion of the CD8+ subset. Cancer Res 47:3317-3321
22. Wersall P, Mellstedt H (1995) Increased LAK and T cell activation in responding renal cell carcinoma patients after low dose cyclophosphamide, IL-2 and alpha-IFN. Med Oncol 12:69-77
23. Pasquier E, Kavallaris M, Andre N (2010) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7:455-465
24. Kerbel RS, Kamen BA (2004) Antiangiogenic basis of low-dose metronomic chemotherapy. Nat Rev Cancer 4:423-436
25. Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, Kerbel RS (2003) Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63:4342-4346
26. Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313:1785-1787
27. Shaked Y, Henke E, Roodhart J, Mancuso P, Langenberg M, Colleoni M, Daenen L, Man S, Xu P, Emmenegger U, Tang T, Zhu Z, Witte L, Bertolini F, Voest E, Benezra R, Kerbel RS (2008) Rapid chemotherapy-induced surge in endothelial progenitor cells: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14:263-273
28. Shaked Y, Kerbel RS (2007) Antiangiogenic strategies on defense: blocking rebound by the tumor vasculature after chemotherapy. Cancer Res 67:7055-7058
29. Man S, Bocci G, Francia G, Green S, Jothy S, Bergers G, Hanahan D, Bohlen P, Hicklin DJ, Kerbel RS (2002) Antitumor and anti-angiogenic effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 62:2731-2735
30. Shaked Y, Cervi D, Neuman M, Pak B, Kerbel RS, Ben-David Y (2005) Splenic microenvironment is a source of angiogenesis/inflammatory mediators accelerating the extramedullary expansion of murine erythroleukemic cells. Blood 105:4500-4507
31. Bocci G, Francia G, Man S, Lawler J, Kerbel RS (2003) Thrombospondin-1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A 100:12917-12922
32. Hamano Y, Sugimoto H, Soubasakos MA, Kieran M, Olsen BR, Lawler J, Sudhakar A, Kalluri R (2004) Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res 64:1570-1574
33. Melillo G (2007) Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26:341-352
34. Melillo G (2006) Inhibiting hypoxia-inducible factor 1 for cancer therapy. Mol Cancer Res 4:601-605
35. Onnis B, Rapisarda A, Melillo G (2009) Development of HIF-1 inhibitors for cancer therapy. J Cell Mol Med 13:2780-2786
36. Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Hewitt SM, Shoemaker RH, Melillo G (2004) Schedule-dependent inhibition of hypoxia-inducible factor-1 alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 64:6845-6848
37. Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G (2004) Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res 64:1475-1482
38. Rapisarda A, Hollingshead M, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Gehrs B, Raffeld M, Kinders RJ, Parchment R, Anver MR, Shoemaker RH, Melillo G (2009) Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther 8:1867-1877
39. Rapisarda A, Melillo G (2009) Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat 12:74-80
40. Rapisarda A, Melillo G (2012) Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 9:378-390
41. Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL (2009) Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci U S A 106:2353-2358
42. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721-732
43. Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F (2004) 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 34:336-344
44. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B (2007) Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56:641-648
45. Couzin-Frankel J (2013) Breakthrough of the year 2013. Cancer immunotherapy. Science 342:1432-1433
46. Lipson EJ (2013) Re-orienting the immune system: durable tumor regression and successful re-induction therapy using anti-PD1 antibodies. Oncoimmunology 2:e23661
47. Rozados VR, Mainetti LE, Rico MJ, Zacarias Fluck MF, Matar P, Scharovsky OG (2010) The immune response and the therapeutic effect of metronomic chemotherapy with cyclophosphamide. Oncol Res 18:601-605
48. Doloff JC, Waxman DJ (2012) VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. Cancer Res 72:1103-1115
49. Ma J, Waxman DJ (2008) Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib. Mol Cancer Ther 7:79-89
50. Cruz-Munoz W, Di DT, Man S, Xu P, Jaramillo ML, Hashimoto K, Collins C, Banville M, O'Connor-McCourt MD, Kerbel RS (2014) Analysis of acquired resistance to metronomic oral topotecan chemotherapy plus pazopanib after prolonged preclinical potent responsiveness in advanced ovarian cancer. Angiogenesis 17:661-673
51. Emmenegger U, Man S, Shaked Y, Francia G, Wong JW, Hicklin DJ, Kerbel RS (2004) A comparative analysis of low dose metronomic cyclophosphamide reveals absent or low grade toxicity on tissues highly sensitive to the toxic effects of maximum tolerated dose regimens. Cancer Res 64:3994-4000
52. Emmenegger U, Morton GC, Francia G, Shaked Y, Franco M, Weinerman A, Man S, Kerbel RS (2006) Low-dose metronomic cyclophosphamide and weekly tirapazamine: a well tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia. Cancer Res 66:1664-1674
53. Emmenegger U, Kerbel RS (2005) A dynamic de-escalating dosing strategy to determine the optimal biological dose for antiangiogenic drugs. Clin Cancer Res 11:7589-7592
54. Emmenegger U, Shaked Y, Man S, Bocci G, Spasojevic I, Francia G, Kouri A, Coke R, Cruz- Munoz W, Ludeman SM, Colvin OM, Kerbel RS (2007) Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice. Mol Cancer Ther 6:2280-2289
55. Emmenegger U, Kerbel RS (2007) Five years of clinical experience with metronomic chemotherapy: achievements and perspectives. Onkologie 30:606-608
56. Emmenegger U, Francia G, Chow A, Shaked Y, Kouri A, Man S, Kerbel RS (2011) Tumors that acquire resistance to metronomic cyclophosphamide retain sensitivity to maximum tolerated dose cyclophosphamide. Neoplasia 13:40-48
57. Hashimoto K, Man S, Xu P, Cruz-Munoz W, Tang T, Kumar R, Kerbel RS (2010) Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer. Mol Cancer Ther 9:996-1006
58. Munoz R, Man S, Shaked Y, Lee C, Wong J, Francia G, Kerbel RS (2006) Highly efficacious non-toxic treatment for advanced metastatic breast cancer using combination UFTcyclophosphamide metronomic chemotherapy. Cancer Res 66:3386-3391
59. Francia G, Cruz-Munoz W, Man S, Xu P, Kerbel RS (2011) Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Cancer 11:135-141
60. Cruz-Munoz W, Man S, Xu P, Kerbel RS (2008) Development of a preclinical model of spontaneous human melanoma central nervous system metastasis. Cancer Res 68:4500-4505
61. Hackl C, Man S, Francia G, Xu P, Kerbel RS (2013) Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models. Gut 62:259-271
62. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth H, Helm W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342
63. Guerin E, Man S, Xu P, Kerbel RS (2013) A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs. Cancer Res 73:2743-2748
64. Al Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983-3988
65. Folkins C, Man S, Shaked Y, Xu P, Hicklin DJ, Kerbel RS (2007) Anti-cancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560-3564
66. Martin-Padura I, Marighetti P, Agliano A, Colombo F, Larzabal L, Redrado M, Bleau AM, Prior C, Bertolini F, Calvo A (2012) Residual dormant cancer stem-cell foci are responsible for tumor relapse after antiangiogenic metronomic therapy in hepatocellular carcinoma xenografts. Lab Invest 92:952-966
67. Vives M, Ginesta MM, Gracova K, Graupera M, Casanovas O, Capella G, Serrano T, Laquente B, Viñals F (2013) Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumor therapy affecting angiogenesis, tumor differentiation and cancer stem cells. Int J Cancer 133:2464-2472
68. Rich JN, Bao S (2007) Chemotherapy and cancer stem cells. Cell Stem Cell 1:353-355
69. 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 23:939-952
70. Fidler IJ, Ellis LM (2000) Chemotherapeutic drugs-more really is not better. Nat Med 6:500-502
71. Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, Kerbel RS, Shaked Y, Mancuso P, Goldhirsch A, Rocca A, Pietri E, Colleoni M (2008) Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer: clinical and biological activity. J Clin Oncol 26:4899-4905
72. Bellmunt J, Trigo JM, Calvo E, Carles J, Perez-Gracia JL, Rubio J, Virizuela JA, Lopez R, Lazaro M, Albanell J (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 11:350-357
73. Koeberie D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D et al (2014) Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: a randomized phase III noninferiority trial (SAKK 41/06). J Clin Oncol Suppl: abstract 3503
74. Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, Groshen S, Swenson S, Markland F, Gandara D, Scudder S, Morgan R, Chen H, Lenz HJ, Oza AM (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 26:76-82
75. Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, Allevi G, Aguggini S, Bodini G, Milani M, Dionisio R, Bernardi C, Montruccoli A, Bruzzi P, Harris AL, Dogliotti L, Berruti A (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 24:3623-3628
76. du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U, Kerbel RS (2006) Strategies for delaying or treating in vivo acquired resistance to trastuzumab (Herceptin®) in human breast cancer xenografts. Clin Cancer Res 12:904-916
77. Rico MJ, Perroud HA, Mainetti LE, Rozados VR, Scharovsky OG (2014) Comparative effectiveness of two metronomic chemotherapy schedules-our experience in the preclinical field. Cancer Invest 32:92-98
78. Mainetti LE, Rico MJ, Fernandez-Zenobi MV, Perroud HA, Roggero EA, Rozados VR, Scharovsky OG (2013) Therapeutic efficacy of metronomic chemotherapy with cyclophosphamide and doxorubicin on murine mammary adenocarcinomas. Ann Oncol 24:2310-2316
79. Perroud HA, Rico MJ, Alasino CM, Queralt F, Mainetti LE, Pezzotto SM, Rozados VR, Scharovsky OG (2013) Safety and therapeutic effect of metronomic chemotherapy with cyclophosphamide and celecoxib in advanced breast cancer patients. Future Oncol 9:451-462
80. Mainetti LE, Rozados VR, Rossa A, Bonfil RD, Scharovsky OG (2011) Antitumoral and antimetastatic effects of metronomic chemotherapy with cyclophosphamide combined with celecoxib on murine mammary adenocarcinomas. J Cancer Res Clin Oncol 137:151-163
81. Bocci G, Tuccori M, Emmenegger U, Liguori V, Kerbel RS, Del Tacca M (2004) Cyclophosphamidemethotrexate "metronomic" chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol 16:1243-1252
82. Orlando L, Cardillo A, Ghisini R, Rocca A, Balduzzi A, Torrisi R, Peruzzotti G, Goldhirsch A, Pietri E, Colleoni M (2006) Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer 6:225
83. Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M (2004) A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350:1713-1721
84. Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y (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 27:1368-1374
85. Kerbel RS (2012) Strategies for improving the clinical benefit of antiangiogenic drug based therapies for breast cancer. J Mammary Gland Biol Neoplasia 17(34):229-239