Метрономная химиотерапия в детской нейроонкологии: взгляд на проблему

1. 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.
2. Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays. 1991;13(1):31-6.
3. Banchi M, Fini E, Crucitta S, Bocci G. Metronomic Chemotherapy in Pediatric Oncology: From Preclinical Evidence to Clinical Studies. J Clin Med. 2022;1-34. DOI:10.3390/jcm11216254.
4. André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol. 2013;14:e239-e48.
5. Pramanik R, Bakhshi S. Metronomic therapy in pediatric oncology: A snapshot. Pediatr Blood Cancer. 2019;66:e27811. DOI:10.1002/pbc.27811.
6. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353-64.
7. Yu JL, Rak J, Carmeliet P, Coomber BL. Heterogenous vascular dependence of  tumour populations. Am J Path. 2001;58:1325-34.
8. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
9. Folkman J, Kalluri R. Tumor Angiogenesis. In: Cancer Medicine. Holland et al., eds. 2000; B.C. Decker Inc. Hamilton, Ontario, Canada. 
10. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med. 1995;1:27-31.
11. Taylor S, Folkman J. Protamine is an inhibitor of angiogenesis. Nature. 1982;297:307-12.
12. Browder T, Butterfield CE, Kraling BM, et al. Anti-angio-genic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res.
2000;60:1878-86. 
13. Chamberlain MC. Recurrent supratentorial malignant gliomas in children. Long-term salvage therapy with oral etoposide. Arch Neurol. 1997;54:554-8.
14. Beecken WDC, Fernandez S, Jouddrn SM, et al. Effect of anti-angiogenic therapy on slowly growing, poorly vascularized tumours in mice. J Natl Cancer Inst. 2001;93:382-7.
15. Spini A, Ciccone V, Rosellini P, et al. Safety of Anti-Angiogenic Drugs in Pediatric Patients with Solid Tumors: A Systematic Review and Meta-Analysis. Cancers. 2022;14:5315. DOI:10.3390/cancers14215315
16. Sie M, Dunnen WFD, Hoving EW, de Bont ES. Anti-angiogenic therapy in pediatric brain tumors: An effective strategy? Crit Rev Oncol. 2014;89:418-32.
17. Ollauri-Ibáñez C, Astigarraga I. Use of Antiangiogenic Therapies in Pediatric Solid Tumors. Cancers. 2021;13:253. DOI:10.3390/cancers13020253
18. Zirlik K, Duyster J. Anti-Angiogenics: Current Situation and Future Perspectives. Oncol Res Treat. 2018;41:166-71.
19. Garcia J, Hurwitz HI, Sandler AB, et al. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev. 2020;86:102017.
20. Petrillo M, Scambia G, Ferrandina G. Novel targets for VEGF-independent anti-angiogenic drugs. Expert Opin Investig Drugs. 2012;21:451-72.
21. Nicolini G, Forini F, Kusmic C, et al. Angiopoietin 2 signal complexity in cardiovascular disease and cancer. Life Sci. 2019;239:117080.
22. Akwii RG, Sajib MS, Zahra FT, Mikelis CM. Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology. Cells. 2019;8:471.
23. Dowlati A, Vlahovic G, Natale RB, et al. A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2016;22:4574-84.
24. Lv PC, Jiang AQ, Zhang WM, Zhu HL. FAK inhibitors in cancer, a patent review. Expert Opin Ther Patents. 2018;28:139-45.
25. De Vinuesa AG, Bocci M, Pietras K, Dijke P. Ten Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function. Biochem Soc Trans. 2016;44:1142-9.
26. Ollauri-Ibáñez C, Núñez-Gómez E, Egido-Turrión C, et al. Continuous endoglin (CD105) overexpression disrupts angiogenesis and facilitates tumor cell metastasis. Angiogenesis. 2020;23:231-47.
27. Uneda S, Toi H, Tsujie T, et al. Anti-endoglin monoclonal antibodies are effective for suppressing metastasis and the primary tumors by targeting tumor vasculature. Int J Cancer. 2009;125:1446-53.
28. Eckerdt F, Clymer J, Bell JB, et al. Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kα inhibition in medulloblastoma. Sci Rep. 2019;9(1):1-11.
29. Chaturvedi NK, Kling MJ, Coulter DW, et al. Improved therapy for medulloblastoma: targeting hedgehog and PI3K-mTOR signaling pathways in combination with chemotherapy. Oncotarget. 2018;9(24):16619.
30. Vo KT, Karski EE, Nasholm NM, et al. Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors. Oncotarget. 2017;8(14):23851.
31. Sterba J, Pavelka Z, Andre N, et al. Second complete remission of relapsed medulloblastoma induced by metronomic chemotherapy. Pediatr Blood Cancer. 2010;54(4):616-7.
32. Peyrl A, Chocholous M, Kieran MW, et al. Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer. 2012;59(3):511-7.
33. Slavc I, Peyrl A, Gojo J, et al. MBCL-43. Reccurent medulloblastoma – long-term survival with a “MEMMAT” based antiangiogenic approach. Neuro-Oncol. 2020;22(Suppl. 3): iii397.
34. Sie M, Dunnen WFD, Hoving EW, de Bont ES. Anti-angiogenic therapy in pediatric brain tumors: An effective strategy? Crit Rev Oncol. 2014;89:418-32.
35. Carcamo B, Francia GJ. Cyclic Metronomic Chemotherapy for Pediatric Tumors: Six Case Reports and a Review of the Literature. J Clin Med. 2022;11(10):2849.
36. Yoshida S, Amano H, Hayashi I, et al. COX-2/VEGF-dependent facilitation of tumor-associated angiogenesis and tumor growth in vivo. Lab Invest. 2003;83(10):1385-94.
37. Pasquier E, Kavallaris M, André N. Metronomic Chemotherapy: New Rationale for New Directions. Nat Rev Clin Oncol. 2010;7:455-65.
38. Highley MS, Landuyt B, Prenen H, et al. Nitrogen Mustards. Pharmacol Rev. 2022;74(3):552-99. DOI:10.1124/pharmrev.120.000121.
39. Bahl A, Bakhshi SJ. Metronomic chemotherapy in progressive pediatric malignancies: old drugs in new package. Indian J Pediatr. 2012;79(12):1617-22.
40. Bocci G, Francia G, Man S, et al. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA. 2003;100:12917-22. 
41. Bocci G, Nicolaou KC, Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res. 2002;62:6938-43.
42. Natale G, Bocci G. Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data. Cancer Lett. 2018;432:28-37.
43. Folkins C, Man S, Xu P, et al. 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. 
44. 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.
45. Liao D, Estévez-Salmerón L, Tlsty TD. Conceptualizing a Tool to Optimize Therapy Based on Dynamic Heterogeneity. Phys Biol. 2012;9(6):065005. 
46. Kerbel RS, Shaked Y. The potential clinical promise of “multimodality” metronomic chemotherapy revealed by preclinical studies of metastatic disease. Cancer Lett.
2017;400:293-304.
47. Sie M, de Bont ESJM, Scherpen FJG, et al. Tumour vasculature and angiogenic profile of paediatric pilocytic astrocytoma; is it much different from glioblastoma? Neuropathol Appl Neurobiol. 2010;36:636-47.
48. Gorsi HS, Khanna P, Tumblin M, et al. Single-agent bevacizumab in the treatment of recurrent or refractory pediatric low-grade glioma: A single institutional experience. Pediatr Blood Cancer. 2018;65:e27234.
49. Verschuur A, Heng-Maillard MA, Dory-Lautrec P, et al. Metronomic Four-Drug Regimen Has Anti-tumor Activity in Pediatric Low-Grade Glioma; The Results of a Phase II Clinical Trial. Front Pharmacol. 2018;9:00950. DOI:10.3389/fphar.2018.00950
50. Kalra M, Heath JA, Kellie SJ, et al. Confirmation of Bevacizumab Activity, and Maintenance of Efficacy in Retreatment After Subsequent Relapse, in Pediatric Low-grade Glioma. J Pediatr Hematol. 2015;37:e341-6.
51. Avery RA, Hwang EI, Jakacki RI, Packer RJ. Marked Recovery of Vision in Children with Optic Pathway Gliomas Treated with Bevacizumab. JAMA Ophthalmol. 2014;132:111-4.
52. Thomas AA, Tucker SM, Nelson CJ, et al. Anaplastic pleomorphic xanthoastrocytoma with leptomeningeal dissemination responsive to BRAF inhibition and bevacizumab. Pediatr Blood Cancer. 2019;66:e27465.
53. Metts RD, Bartynski W, Welsh CT, et al. Bevacizumab Therapy for Pilomyxoid Astrocytoma. J Pediatr Hematol. 2017;39:e219-23.
54. Legault G, Kieran MW, Scott RM, et al. Recurrent Ascites in a Patient with Low-grade Astrocytoma and Ventriculo-Peritoneal Shunt Treated with the Multikinase Inhibitor Sorafenib. J Pediatr Hematol. 2014;36:e533-5.
55. Slavc I, Mayr L, Stepien N, et al. Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a “MEMMAT-like” Metronomic Antiangiogenic Approach. Cancers. 2022;14:5128. DOI:10.3390/cancers14205128
56. Thompson EM, Keir ST, Venkatraman T, et al. The role of angiogenesis in Group 3 medulloblastoma pathogenesis and survival. Neuro-Oncology 2017;19:1217-27.
57. Levy AS, Krailo M, Chi S, et al. Temozolomide with Irinotecan versus Temozolomide, Irinotecan plus Bevacizumab for Recurrent Medulloblastoma of Childhood: Report of a COG Randomized Phase II Screening Trial. Pediatr Blood Cancer. 2021;68:e29031.
58. Aguilera D, Mazewski C, Fangusaro J, et al. Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: A multi-institutional experience. Child’s Nerv Syst. 2013;29:589-96.
59. Piha-Paul SA, Shin SJ, Vats T, et al. Pediatric patients with refractory central nervous system tumors: Experiences of a clinical trial combining bevacizumab and temsirolimus. Anticancer Res. 2014;34:1939-45.
60. Fleischhack G, Jaehde U, Bode U. Pharmacokinetics Following Intraventricular Administration of Chemotherapy in Patients with Neoplastic Meningitis. Clin Pharmacokinet. 2005;44:1-31.
61. Korshunov A, Sahm F, Zheludkova O, et al. DNA Methylation Profiling Is a Method of Choice for Molecular Verification of Pediatric WNT-Activated Medulloblastomas. Neuro-Oncol. 2019;21:214-21.
62. Slavc I, Schuller E, Falger J, et al. Feasibility of Long-Term Intraventricular Therapy with Mafosfamide (n = 26) and Etoposide (n = 11): Experience in 26 Children with Disseminated Malignant Brain Tumors. J Neurooncol. 2003;64:239-47.
63. Gupta T, Maitre M, Sastri GJ, et al. Outcomes of Salvage Re-Irradiation in Recurrent Medulloblastoma Correlate with Age at Initial Diagnosis, Primary Risk-Stratification, and Molecular Subgrouping. J Neurooncol. 2019;144:283-91. 
64. Tsang DS, Sarhan N, Ramaswamy V, et al. Re-Irradiation for Children with Recurrent Medulloblastoma in Toronto, Canada: A 20-Year Experience. J Neurooncol. 2019;145:107-14. 
65. Kumar R, Smith KS, Deng M, et al. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma. J Clin Oncol Off J Am Soc Clin Oncol.
2021;39:807-21.
66. Šterba J, Pavelka Z, Šlampa P. Concomitant radiotherapy and metronomic temozolomide in pediatric high-risk brain tumors. Neoplasma. 2002;49:117-20.
67. Pasqualini C, Rubino J, Brard C, et al. Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSé-ESMART, a trial of the European Innovative Therapies for Children With Cance. Eur J Cancer. 2021;150:53-62. 
68. Zapletalova D, Andr N, Deak L, et al. Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: A multicenter experience. Oncology. 2012;82:249-60.
69. Craveiro RB, Ehrhardt M, Holst M, et al. In comparative analysis of multi-kinase inhibitors for targeted medulloblastoma therapy pazopanib exhibits promising in vitro and in vivo efficacy. Oncotarget. 2014;5:7149.
70. Abouantoun TJ, Castellino RC, Macdonald TJ. Sunitinib induces PTEN expression and inhibits PDGFR signaling and migration of medulloblastoma cells. J Neuro-Oncol. 2010;101:215-26.
71. Adolph JE, Fleischhack G, Gaab C, et al. Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies. J Neurooncol. 2021;155(2):193-202. DOI:10.1007/s11060-021-03867-8
72. Renzi S, Michaeli O, Salvador H, et al. Bevacizumab for NF2-associated vestibular schwannomas of childhood and adolescence. Pediatr Blood Cancer. 2020;67(5):e28228. DOI:10.1002/pbc.28228
73. DePrimo SE, Bello C. Surrogate biomarkers in evaluating response to anti-angiogenic agents: focus on sunitinib. Ann Oncol. 2007;18 (Suppl. 10):x11-9. DOI:10.1093/annonc/mdm409
74. Pilotto C, Beshlawi I, Thomas A, Grundy RG. Vascular stenosis in a child with visual pathway glioma treated with bevacizumab: A case report and review of literature. Child’s Nerv Syst. 2017;34:781-5.
75. Hwang EI, Jakacki RI, Fisher MJ, et al. Long-term efficacy and toxicity of bevacizumab-based therapy in children with recurrent low-grade gliomas. Pediatr Blood Cancer. 2013;60(5):776-82. DOI:10.1002/pbc.24297
76. De Vita S, De Matteis S, Laurenti L, et al. Secondary Ph+ acute lymphoblastic leukemia after temozolomide. Ann Hematol. 2005;84(11):760-2.

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1. 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.
2. Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays. 1991;13(1):31-6.
3. Banchi M, Fini E, Crucitta S, Bocci G. Metronomic Chemotherapy in Pediatric Oncology: From Preclinical Evidence to Clinical Studies. J Clin Med. 2022;1-34. DOI:10.3390/jcm11216254.
4. André N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol. 2013;14:e239-e48.
5. Pramanik R, Bakhshi S. Metronomic therapy in pediatric oncology: A snapshot. Pediatr Blood Cancer. 2019;66:e27811. DOI:10.1002/pbc.27811.
6. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353-64.
7. Yu JL, Rak J, Carmeliet P, Coomber BL. Heterogenous vascular dependence of  tumour populations. Am J Path. 2001;58:1325-34.
8. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.
9. Folkman J, Kalluri R. Tumor Angiogenesis. In: Cancer Medicine. Holland et al., eds. 2000; B.C. Decker Inc. Hamilton, Ontario, Canada. 
10. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature Med. 1995;1:27-31.
11. Taylor S, Folkman J. Protamine is an inhibitor of angiogenesis. Nature. 1982;297:307-12.
12. Browder T, Butterfield CE, Kraling BM, et al. Anti-angio-genic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res.
2000;60:1878-86. 
13. Chamberlain MC. Recurrent supratentorial malignant gliomas in children. Long-term salvage therapy with oral etoposide. Arch Neurol. 1997;54:554-8.
14. Beecken WDC, Fernandez S, Jouddrn SM, et al. Effect of anti-angiogenic therapy on slowly growing, poorly vascularized tumours in mice. J Natl Cancer Inst. 2001;93:382-7.
15. Spini A, Ciccone V, Rosellini P, et al. Safety of Anti-Angiogenic Drugs in Pediatric Patients with Solid Tumors: A Systematic Review and Meta-Analysis. Cancers. 2022;14:5315. DOI:10.3390/cancers14215315
16. Sie M, Dunnen WFD, Hoving EW, de Bont ES. Anti-angiogenic therapy in pediatric brain tumors: An effective strategy? Crit Rev Oncol. 2014;89:418-32.
17. Ollauri-Ibáñez C, Astigarraga I. Use of Antiangiogenic Therapies in Pediatric Solid Tumors. Cancers. 2021;13:253. DOI:10.3390/cancers13020253
18. Zirlik K, Duyster J. Anti-Angiogenics: Current Situation and Future Perspectives. Oncol Res Treat. 2018;41:166-71.
19. Garcia J, Hurwitz HI, Sandler AB, et al. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev. 2020;86:102017.
20. Petrillo M, Scambia G, Ferrandina G. Novel targets for VEGF-independent anti-angiogenic drugs. Expert Opin Investig Drugs. 2012;21:451-72.
21. Nicolini G, Forini F, Kusmic C, et al. Angiopoietin 2 signal complexity in cardiovascular disease and cancer. Life Sci. 2019;239:117080.
22. Akwii RG, Sajib MS, Zahra FT, Mikelis CM. Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology. Cells. 2019;8:471.
23. Dowlati A, Vlahovic G, Natale RB, et al. A Phase I, First-in-Human Study of AMG 780, an Angiopoietin-1 and -2 Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2016;22:4574-84.
24. Lv PC, Jiang AQ, Zhang WM, Zhu HL. FAK inhibitors in cancer, a patent review. Expert Opin Ther Patents. 2018;28:139-45.
25. De Vinuesa AG, Bocci M, Pietras K, Dijke P. Ten Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function. Biochem Soc Trans. 2016;44:1142-9.
26. Ollauri-Ibáñez C, Núñez-Gómez E, Egido-Turrión C, et al. Continuous endoglin (CD105) overexpression disrupts angiogenesis and facilitates tumor cell metastasis. Angiogenesis. 2020;23:231-47.
27. Uneda S, Toi H, Tsujie T, et al. Anti-endoglin monoclonal antibodies are effective for suppressing metastasis and the primary tumors by targeting tumor vasculature. Int J Cancer. 2009;125:1446-53.
28. Eckerdt F, Clymer J, Bell JB, et al. Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kα inhibition in medulloblastoma. Sci Rep. 2019;9(1):1-11.
29. Chaturvedi NK, Kling MJ, Coulter DW, et al. Improved therapy for medulloblastoma: targeting hedgehog and PI3K-mTOR signaling pathways in combination with chemotherapy. Oncotarget. 2018;9(24):16619.
30. Vo KT, Karski EE, Nasholm NM, et al. Phase 1 study of sirolimus in combination with oral cyclophosphamide and topotecan in children and young adults with relapsed and refractory solid tumors. Oncotarget. 2017;8(14):23851.
31. Sterba J, Pavelka Z, Andre N, et al. Second complete remission of relapsed medulloblastoma induced by metronomic chemotherapy. Pediatr Blood Cancer. 2010;54(4):616-7.
32. Peyrl A, Chocholous M, Kieran MW, et al. Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer. 2012;59(3):511-7.
33. Slavc I, Peyrl A, Gojo J, et al. MBCL-43. Reccurent medulloblastoma – long-term survival with a “MEMMAT” based antiangiogenic approach. Neuro-Oncol. 2020;22(Suppl. 3): iii397.
34. Sie M, Dunnen WFD, Hoving EW, de Bont ES. Anti-angiogenic therapy in pediatric brain tumors: An effective strategy? Crit Rev Oncol. 2014;89:418-32.
35. Carcamo B, Francia GJ. Cyclic Metronomic Chemotherapy for Pediatric Tumors: Six Case Reports and a Review of the Literature. J Clin Med. 2022;11(10):2849.
36. Yoshida S, Amano H, Hayashi I, et al. COX-2/VEGF-dependent facilitation of tumor-associated angiogenesis and tumor growth in vivo. Lab Invest. 2003;83(10):1385-94.
37. Pasquier E, Kavallaris M, André N. Metronomic Chemotherapy: New Rationale for New Directions. Nat Rev Clin Oncol. 2010;7:455-65.
38. Highley MS, Landuyt B, Prenen H, et al. Nitrogen Mustards. Pharmacol Rev. 2022;74(3):552-99. DOI:10.1124/pharmrev.120.000121.
39. Bahl A, Bakhshi SJ. Metronomic chemotherapy in progressive pediatric malignancies: old drugs in new package. Indian J Pediatr. 2012;79(12):1617-22.
40. Bocci G, Francia G, Man S, et al. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci USA. 2003;100:12917-22. 
41. Bocci G, Nicolaou KC, Kerbel RS. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res. 2002;62:6938-43.
42. Natale G, Bocci G. Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data. Cancer Lett. 2018;432:28-37.
43. Folkins C, Man S, Xu P, et al. 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. 
44. 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.
45. Liao D, Estévez-Salmerón L, Tlsty TD. Conceptualizing a Tool to Optimize Therapy Based on Dynamic Heterogeneity. Phys Biol. 2012;9(6):065005. 
46. Kerbel RS, Shaked Y. The potential clinical promise of “multimodality” metronomic chemotherapy revealed by preclinical studies of metastatic disease. Cancer Lett.
2017;400:293-304.
47. Sie M, de Bont ESJM, Scherpen FJG, et al. Tumour vasculature and angiogenic profile of paediatric pilocytic astrocytoma; is it much different from glioblastoma? Neuropathol Appl Neurobiol. 2010;36:636-47.
48. Gorsi HS, Khanna P, Tumblin M, et al. Single-agent bevacizumab in the treatment of recurrent or refractory pediatric low-grade glioma: A single institutional experience. Pediatr Blood Cancer. 2018;65:e27234.
49. Verschuur A, Heng-Maillard MA, Dory-Lautrec P, et al. Metronomic Four-Drug Regimen Has Anti-tumor Activity in Pediatric Low-Grade Glioma; The Results of a Phase II Clinical Trial. Front Pharmacol. 2018;9:00950. DOI:10.3389/fphar.2018.00950
50. Kalra M, Heath JA, Kellie SJ, et al. Confirmation of Bevacizumab Activity, and Maintenance of Efficacy in Retreatment After Subsequent Relapse, in Pediatric Low-grade Glioma. J Pediatr Hematol. 2015;37:e341-6.
51. Avery RA, Hwang EI, Jakacki RI, Packer RJ. Marked Recovery of Vision in Children with Optic Pathway Gliomas Treated with Bevacizumab. JAMA Ophthalmol. 2014;132:111-4.
52. Thomas AA, Tucker SM, Nelson CJ, et al. Anaplastic pleomorphic xanthoastrocytoma with leptomeningeal dissemination responsive to BRAF inhibition and bevacizumab. Pediatr Blood Cancer. 2019;66:e27465.
53. Metts RD, Bartynski W, Welsh CT, et al. Bevacizumab Therapy for Pilomyxoid Astrocytoma. J Pediatr Hematol. 2017;39:e219-23.
54. Legault G, Kieran MW, Scott RM, et al. Recurrent Ascites in a Patient with Low-grade Astrocytoma and Ventriculo-Peritoneal Shunt Treated with the Multikinase Inhibitor Sorafenib. J Pediatr Hematol. 2014;36:e533-5.
55. Slavc I, Mayr L, Stepien N, et al. Improved Long-Term Survival of Patients with Recurrent Medulloblastoma Treated with a “MEMMAT-like” Metronomic Antiangiogenic Approach. Cancers. 2022;14:5128. DOI:10.3390/cancers14205128
56. Thompson EM, Keir ST, Venkatraman T, et al. The role of angiogenesis in Group 3 medulloblastoma pathogenesis and survival. Neuro-Oncology 2017;19:1217-27.
57. Levy AS, Krailo M, Chi S, et al. Temozolomide with Irinotecan versus Temozolomide, Irinotecan plus Bevacizumab for Recurrent Medulloblastoma of Childhood: Report of a COG Randomized Phase II Screening Trial. Pediatr Blood Cancer. 2021;68:e29031.
58. Aguilera D, Mazewski C, Fangusaro J, et al. Response to bevacizumab, irinotecan, and temozolomide in children with relapsed medulloblastoma: A multi-institutional experience. Child’s Nerv Syst. 2013;29:589-96.
59. Piha-Paul SA, Shin SJ, Vats T, et al. Pediatric patients with refractory central nervous system tumors: Experiences of a clinical trial combining bevacizumab and temsirolimus. Anticancer Res. 2014;34:1939-45.
60. Fleischhack G, Jaehde U, Bode U. Pharmacokinetics Following Intraventricular Administration of Chemotherapy in Patients with Neoplastic Meningitis. Clin Pharmacokinet. 2005;44:1-31.
61. Korshunov A, Sahm F, Zheludkova O, et al. DNA Methylation Profiling Is a Method of Choice for Molecular Verification of Pediatric WNT-Activated Medulloblastomas. Neuro-Oncol. 2019;21:214-21.
62. Slavc I, Schuller E, Falger J, et al. Feasibility of Long-Term Intraventricular Therapy with Mafosfamide (n = 26) and Etoposide (n = 11): Experience in 26 Children with Disseminated Malignant Brain Tumors. J Neurooncol. 2003;64:239-47.
63. Gupta T, Maitre M, Sastri GJ, et al. Outcomes of Salvage Re-Irradiation in Recurrent Medulloblastoma Correlate with Age at Initial Diagnosis, Primary Risk-Stratification, and Molecular Subgrouping. J Neurooncol. 2019;144:283-91. 
64. Tsang DS, Sarhan N, Ramaswamy V, et al. Re-Irradiation for Children with Recurrent Medulloblastoma in Toronto, Canada: A 20-Year Experience. J Neurooncol. 2019;145:107-14. 
65. Kumar R, Smith KS, Deng M, et al. Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma. J Clin Oncol Off J Am Soc Clin Oncol.
2021;39:807-21.
66. Šterba J, Pavelka Z, Šlampa P. Concomitant radiotherapy and metronomic temozolomide in pediatric high-risk brain tumors. Neoplasma. 2002;49:117-20.
67. Pasqualini C, Rubino J, Brard C, et al. Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSé-ESMART, a trial of the European Innovative Therapies for Children With Cance. Eur J Cancer. 2021;150:53-62. 
68. Zapletalova D, Andr N, Deak L, et al. Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: A multicenter experience. Oncology. 2012;82:249-60.
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Ю.В. Диникина*¹, О.Г. Желудкова², М.В. Рыжова³, Л.В. Ольхова⁴, Д.Ю. Корнеев², М.Б. Белогурова<sup>1

1</sup>ФГБУ «Национальный медицинский исследовательский центр им. В.А. Алмазова» Минздрава России, Санкт-Петербург, Россия;
²ГБУЗ «Научно-практический центр специализированной медицинской помощи им. В.Ф. Войно-Ясенецкого» Департамента здравоохранения г. Москвы, Москва, Россия;
³ФГАУ «Национальный медицинский исследовательский центр нейрохирургии им. акад. Н.Н. Бурденко» Минздрава России, Москва, Россия;
⁴Российская детская клиническая больница – филиал ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия
*dinikinayulia@mail.ru

________________________________________________

Yulia V. Dinikina*¹, Olga G. Zheludkova², Marina V. Ryzhova³, Liudmila V. Olhova⁴, Denis Yu. Korneev², Margarita B. Belogurova<sup>1

1</sup>Almazov National Medical Research Centre, Saint Petersburg, Russia;
²Voino-Yasenetskiy Scientific and Practical Center of Specialized Healthсare for Children, Moscow, Russia;
³Burdenko National Medical Research Center for Neurosurgery, Moscow, Russia;
⁴Russian Children’s Clinical Hospital – branch of Pirogov Russian National Research Medical University, Moscow, Russia
*dinikinayulia@mail.ru