METRONOMIC CHEMOTHERAPY
DOI:
https://doi.org/10.14456/tbps.2020.2Keywords:
metronomic chemotherapy, anti-angiogenesis, activation of immunityAbstract
Conventional chemotherapy, which is given in cycles of maximum tolerated dosages, can cause toxic side-effects and drug resistance that limits clinical use of these drugs with cancer patients. To address these problems, researchers are investigating a new modality of chemotherapeutic drug regimens known as metronomic chemotherapy (MCT). The new dosing schedule involves continuous administration of conventional chemotherapeutic drugs at low doses for longer periods, without a lengthy drug-free period, when compared with conventional chemotherapy. This is done to inhibit the function of activated tumor endothelial cells in numerous cancers. When these new regimens destroy tumor angiogenesis and the formation of new blood vessel tumor cells, nutrients and oxygen cannot be supplied to the tumors which results in indirect inhibition of tumor growth and metastasis. The new regimens are beneficial to minimize adverse effects, reduce risk of developing acquired drug resistance, and improve quality of life in both adult and pediatric patients. Recently, the mechanism of MCT actions, which were studied at preclinical and clinical levels, described MCT as a multi-targeted therapy that inhibited tumor angiogenesis, restored anticancer immune response, and induction of tumor dormancy. Herein, this article reviews fundamental facts, mechanism of actions, chemotherapeutic drugs used in clinical trials as well as limitations of a low dose regimen for metronomic chemotherapy.
References
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21. Banissi C, Ghiringhelli F, Chen L, Carpentier AF. Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother. 2009;58:1627-34.
22. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. 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. 2007;56:641–8.
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25. Natalea G, Bocci G. Does metronomic chemotherapy induce tumor angiogenic dormancy? a review of available preclinical and clinical data. Cancer Lett. 2018;432:28–37.
26. Schwarze SR, Fu VX, Desotelle JA, Kenowski ML, Jarrard DF. The identification of senescence-specific genes during the induction of senescence in prostate cancer cells. Neoplasia. 2005;7(9):816-23.
27. André N, Pasquier E. Response to “Intermittent androgen blockade should be regarded as standard therapy in prostate cancer”. Nat Clin Pract Oncol. 2009;6(2) :E1.
28. Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol. 2010;7(8):455-65.
29. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 2007;67:3560-4.
30. Vives M, Ginestà MM, Gracova K, Graupera M, Casanovas O, Capellà G. Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells. Int J Cancer. 2013;133:2464-72.
31. Smith AJ, Oertle J, Prato D. Novel approach to chemotherapy and administration selection with metronomic/fractionated dosing. J Cancer Ther. 2015;6(5):455-65.
32. Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, et al. Cyclophosphamide –methotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol. 2005;16:1243–52.
33. Liu Y, Gu F, Liang J, Dai X, Wan C, Hong X, et al. The efficacy and toxicity profile of metronomic chemotherapy for metastatic breast cancer: a meta-analysis. PLoS ONE. 2017;12(3):e0173693.
34. Muthusamy P, Chary KV, Nalini G. Metronomic chemotherapy: Seems prowess to battle against cancer in current scenario. J Clin Diagn Res. 2016;10(11):FC9-13.
35. Bahl A, Bakhshi S. Metronomic chemotherapy in progressive pediatric malignancies: old drugs in new package. Indian J Pediatr. 2012;79:1617-22.
36. Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F, et al. Low dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002;13:73-80.
37. Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, 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(1):76-82.
38. Franssen LE, Nijhof IS, Bjorklund CC, Chiu H, Doorn R, van Velzen J, et al. Lenalidomide combined with low-dose cyclophosphamide and prednisone modulates Ikaros and Aiolos in lymphocytes, resulting in immunostimulatory effects in lenalidomide refractory multiple myeloma patients. Oncotarget. 2018;9(74):34009-21.
39. Fontana A, Galli L, Fioravanti A, Orlandi P, Galli C, Landi L, et al. Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res. 2009;15:4954-62.
40. Buckstein R, Kerbel RS, Shaked Y, Nayar R, Foden C, Turner R, et al. High-dose celecoxib and metronomic "low-dose" cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin's lymphoma. Clin Cancer Res. 2006;12:5190-8.
41. Sterba J, Valik D, Mudry P, Kepak T, Pavelka Z, Bajciova V, et al. Combined biodifferentiating and antiangiogenic oral metronomic therapy is feasible and effective in relapsed solid tumors in children: single-center pilot study. Onkologie. 2006;29:308–13.
42. Ali AM, El-Sayed MI. Metronomic chemotherapy and radiotherapy as salvage treatment in refractory or relapsed pediatric solid tumours. Curr Oncol. 2016;23(3):e253-59.
43. Choi LM, Rood B, Kamani N, La Fond D, Packer RJ, Santi MR, et al. Feasibility of metronomic maintenance chemotherapy following high-dose chemotherapy for malignant central nervous system tumors. Pediatr Blood Cancer. 2008;50(5):970-5.
44. Minturn JE, Janss AJ, Fisher PG, Allen JC, Patti R, Phillips PC, et al. A phase II study of metronomic oral topotecan for recurrent childhood brain tumors. Pediatr Blood Cancer. 2011;56(1):39–44.
2. Yadav L, Puri N, Rastogi V, Satpute P, Sharma V. Tumour angiogenesis and angiogenic inhibitors: a review. J Clin Diagn Res. 2015;9(6):XE1-5.
3. Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2011;2(12):1097-105.
4. Simsek C, Esin E, Yalcin S. Metronomic chemotherapy: a systematic review of the literature and clinical experience. J Oncol. 2019;2019:5483791.
5. Maiti R. Metronomic chemotherapy. J Pharmacol Pharmacother. 2014;5(3):186-92.
6. Scharovsky OG, Mainetti LE, Rozados VR. Metronomic chemotherapy: changing the paradigm that more is better. Curr Oncol. 2009;16(2):7-15.
7. Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O'Reilly MS, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60:1878-86.
8. Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, 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(8):R15-24.
9. Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105(8):1045–7.
10. National Cancer Institute [Internet]. Bethesda (MD): the Institute; c2019. NCI Dictionary of Cancer Terms, metronomic chemotherapy [cited 2019 Jul 15]. Available from:https://www.cancer.gov/publications/dictionaries/cancer-terms/def/metronomic-therapy
11. Lien K, Georgsdottir S, Sivanathan L, Chan K, Emmenegger U. Low-dose metronomic chemotherapy: a systematic literature analysis. Eur J Cancer. 2013;49(16):3387-95.
12. Fremder E, Shaked Y. Mechanisms of action of low-dose metronomic chemotherapy. In: Bocci G, Francia G, editors. Metronomic chemotherapy: pharmacology and clinical applications. New York: Springer; 2014. p.23-38.
13. Kareva I, Waxman DJ, Klement GL. Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance. Cancer Lett. 2015;358:100–6.
14. Huang T, Sun L, Yuan X, Qiu H. Thrombospondin-1 is a multifaceted player in tumor progression. Oncotarget. 2017;8(48):84546-58.
15. Mpekris F, Baish JW, Stylianopoulos T, Jain RK. Role of vascular normalization in benefit from metronomic chemotherapy. Proc Natl Acad Sci USA. 2017;114(8):1994-9.
16. Abu Lila AS, Ishida T. Metronomic chemotherapy and nanocarrier platforms. Cancer Lett. 2017;400:232-42.
17. Chen YL, Chang MC, Cheng WF. Metronomic chemotherapy and immunotherapy in cancer treatment. Cancer Lett. 2017;400:282-92.
18. Biziota E, Mavroeidis L, Hatzimichael E, Pappas P. Metronomic chemotherapy: a potent macerator of cancer by inducing angiogenesis suppression and antitumor immune activation. Cancer Lett. 2017;400:243-51.
19. Hao YB, Yi SY, Ruan J, Zhao L, Nan KJ. New insights into metronomic chemotherapy-induced immunoregulation. Cancer Lett. 2014;354:220-6.
20. 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(7):2862-8.
21. Banissi C, Ghiringhelli F, Chen L, Carpentier AF. Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol Immunother. 2009;58:1627-34.
22. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, et al. 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. 2007;56:641–8.
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.
24. UPMC Hillman Cancer Center. Understanding bone marrow suppression during cancer treatment [Internet]. Pittsburgh (PA): UPMC HealthBeat; 2015 [updated 2015 Mar 16; cited 2019 Jul 15]. Available from: https://share.upmc.com/2015/03/ understanding-bone-marrow-suppression-during-cancer-treatment/
25. Natalea G, Bocci G. Does metronomic chemotherapy induce tumor angiogenic dormancy? a review of available preclinical and clinical data. Cancer Lett. 2018;432:28–37.
26. Schwarze SR, Fu VX, Desotelle JA, Kenowski ML, Jarrard DF. The identification of senescence-specific genes during the induction of senescence in prostate cancer cells. Neoplasia. 2005;7(9):816-23.
27. André N, Pasquier E. Response to “Intermittent androgen blockade should be regarded as standard therapy in prostate cancer”. Nat Clin Pract Oncol. 2009;6(2) :E1.
28. Pasquier E, Kavallaris M, André N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol. 2010;7(8):455-65.
29. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 2007;67:3560-4.
30. Vives M, Ginestà MM, Gracova K, Graupera M, Casanovas O, Capellà G. Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells. Int J Cancer. 2013;133:2464-72.
31. Smith AJ, Oertle J, Prato D. Novel approach to chemotherapy and administration selection with metronomic/fractionated dosing. J Cancer Ther. 2015;6(5):455-65.
32. Bocci G, Tuccori M, Emmenegger U, Liguori V, Falcone A, Kerbel RS, et al. Cyclophosphamide –methotrexate ‘metronomic’ chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol. 2005;16:1243–52.
33. Liu Y, Gu F, Liang J, Dai X, Wan C, Hong X, et al. The efficacy and toxicity profile of metronomic chemotherapy for metastatic breast cancer: a meta-analysis. PLoS ONE. 2017;12(3):e0173693.
34. Muthusamy P, Chary KV, Nalini G. Metronomic chemotherapy: Seems prowess to battle against cancer in current scenario. J Clin Diagn Res. 2016;10(11):FC9-13.
35. Bahl A, Bakhshi S. Metronomic chemotherapy in progressive pediatric malignancies: old drugs in new package. Indian J Pediatr. 2012;79:1617-22.
36. Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F, et al. Low dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002;13:73-80.
37. Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, 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(1):76-82.
38. Franssen LE, Nijhof IS, Bjorklund CC, Chiu H, Doorn R, van Velzen J, et al. Lenalidomide combined with low-dose cyclophosphamide and prednisone modulates Ikaros and Aiolos in lymphocytes, resulting in immunostimulatory effects in lenalidomide refractory multiple myeloma patients. Oncotarget. 2018;9(74):34009-21.
39. Fontana A, Galli L, Fioravanti A, Orlandi P, Galli C, Landi L, et al. Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res. 2009;15:4954-62.
40. Buckstein R, Kerbel RS, Shaked Y, Nayar R, Foden C, Turner R, et al. High-dose celecoxib and metronomic "low-dose" cyclophosphamide is an effective and safe therapy in patients with relapsed and refractory aggressive histology non-Hodgkin's lymphoma. Clin Cancer Res. 2006;12:5190-8.
41. Sterba J, Valik D, Mudry P, Kepak T, Pavelka Z, Bajciova V, et al. Combined biodifferentiating and antiangiogenic oral metronomic therapy is feasible and effective in relapsed solid tumors in children: single-center pilot study. Onkologie. 2006;29:308–13.
42. Ali AM, El-Sayed MI. Metronomic chemotherapy and radiotherapy as salvage treatment in refractory or relapsed pediatric solid tumours. Curr Oncol. 2016;23(3):e253-59.
43. Choi LM, Rood B, Kamani N, La Fond D, Packer RJ, Santi MR, et al. Feasibility of metronomic maintenance chemotherapy following high-dose chemotherapy for malignant central nervous system tumors. Pediatr Blood Cancer. 2008;50(5):970-5.
44. Minturn JE, Janss AJ, Fisher PG, Allen JC, Patti R, Phillips PC, et al. A phase II study of metronomic oral topotecan for recurrent childhood brain tumors. Pediatr Blood Cancer. 2011;56(1):39–44.
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