Metronomic chemotherapy in pediatric neurooncology: insight the problem. A review

Cover Page

Cite item

Full Text

Abstract

Metronomic chemotherapy (MCT) is a promising direction of anticancer therapy, as well as in pediatric oncology, and its administration in patients with refractory and recurrent tumors of the central nervous system becomes increasingly relevant. Being a regimen of low doses of antitumor agents with different mechanisms of action in a continuous mode for a long time, it allows to overcome the resistance of tumor cells and to minimize the toxic effects of treatment. Today, the issues of rational choice of MCT regimens, which are dependent on the type of tumor, and the application of biomarkers of its effectiveness, remain controversial. The article discusses in detail the biological effects of MCT with an accent on antiangiogenic one, as well as the possibilities and limitations of MCT application in pediatric practice and the results of studies in tumors of the central nervous system.

About the authors

Yulia V. Dinikina

Almazov National Medical Research Centre

Author for correspondence.
Email: dinikinayulia@mail.ru
ORCID iD: 0000-0002-2003-0982

Cand. Sci. (Med.)

Russian Federation, Saint Petersburg

Olga G. Zheludkova

Voino-Yasenetskiy Scientific and Practical Center of Specialized Healthсare for Children

Email: clelud@mail.ru
ORCID iD: 0000-0002-8607-3635

D. Sci. (Med.), Prof.

Russian Federation, Moscow

Marina V. Ryzhova

Burdenko National Medical Research Center for Neurosurgery

Email: mrizhova@nsi.ru

D. Sci. (Med.)

Russian Federation, Moscow

Liudmila V. Olhova

Russian Children’s Clinical Hospital – branch of Pirogov Russian National Research Medical University

Email: rylkova87@mail.ru
ORCID iD: 0000-0002-7531-6443

pediatric oncologist

Russian Federation, Moscow

Denis Yu. Korneev

Voino-Yasenetskiy Scientific and Practical Center of Specialized Healthсare for Children

Email: elldecor2016@gmail.com

pediatric oncologist

Russian Federation, Moscow

Margarita B. Belogurova

Almazov National Medical Research Centre

Email: deton.hospital31@inbox.ru
ORCID iD: 0000-0002-7471-7181

D. Sci. (Med.), Prof.

Russian Federation, Saint Petersburg

References

  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.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Major targets for angiogenesis inhibitors [adapted from 17].

Download (343KB)
Indexing metadata
3. Fig. 2. Basic mechanisms for realizing the antitumor effect of metronomic regimens of cyclophosphamide (adapted from [38]).

Download (157KB)
Indexing metadata

Copyright (c) 2024 Consilium Medicum

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
 


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies