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Vol 73, No 5 (2023)
Review paper
Published online: 2023-09-04
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Methotrexate-associated oral mucositis in children with acute lymphoblastic leukemia

Ewa Pustelnik1, Katarzyna Pikora1, Katarzyna Pawelec2
DOI: 10.5603/njo.96144
·
Nowotwory. Journal of Oncology 2023;73(5):294-302.
Affiliations
  1. Infant Jesus Clinical Hospital of the University Clinical Center, Medical University of Warsaw, Warsaw, Poland
  2. Department of Oncology, Pediatric Hematology, Clinical Transplantology and Pediatric, University Clinical Center, Medical University of Warsaw, Warsaw, Poland

open access

Vol 73, No 5 (2023)
Review articles – Leukemia
Published online: 2023-09-04

Abstract

Methotrexate is an antifolate widely used in oncology and rheumatology that plays an important role in the treatment of acute lymphoblastic leukemia in children. One of its most common side effects is oral mucositis, which is a general term for ulceration and inflammation of the mucous membrane of the mouth. It can severely affect a patient’s quality of life, causes poor nutrition, and may lead to discontinuation of the next course of chemotherapy. Oral mucositis typically develops a few days after chemotherapy infusion. Due to this risk, it appears reasonable to use preventive agents against oral mucositis before the inclusion of methotrexate in therapy. To date, clinical trials have examined the effectiveness of medications such as glutamine, palifermin, chlorhexidine, amifostine, cyclooxygenase-1 inhibitor, leucovorin or other methods including laser therapy and oral cryotherapy. There are also several methods used to control already established inflammation and reduce pain more effectively: laser therapy, platelet-rich plasma and platelet gel, taxifolin, film-forming and coating agents. A crucial role is played by supportive interventions involving analgesic treatment, including topical morphine and benzydamine and a modern approach to pain management – for example, the use of virtual reality.

Abstract

Methotrexate is an antifolate widely used in oncology and rheumatology that plays an important role in the treatment of acute lymphoblastic leukemia in children. One of its most common side effects is oral mucositis, which is a general term for ulceration and inflammation of the mucous membrane of the mouth. It can severely affect a patient’s quality of life, causes poor nutrition, and may lead to discontinuation of the next course of chemotherapy. Oral mucositis typically develops a few days after chemotherapy infusion. Due to this risk, it appears reasonable to use preventive agents against oral mucositis before the inclusion of methotrexate in therapy. To date, clinical trials have examined the effectiveness of medications such as glutamine, palifermin, chlorhexidine, amifostine, cyclooxygenase-1 inhibitor, leucovorin or other methods including laser therapy and oral cryotherapy. There are also several methods used to control already established inflammation and reduce pain more effectively: laser therapy, platelet-rich plasma and platelet gel, taxifolin, film-forming and coating agents. A crucial role is played by supportive interventions involving analgesic treatment, including topical morphine and benzydamine and a modern approach to pain management – for example, the use of virtual reality.

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Keywords

leukemia; methotrexate; chemotherapy; oral mucositis

About this article
Title

Methotrexate-associated oral mucositis in children with acute lymphoblastic leukemia

Journal

Nowotwory. Journal of Oncology

Issue

Vol 73, No 5 (2023)

Article type

Review paper

Pages

294-302

Published online

2023-09-04

Page views

494

Article views/downloads

384

DOI

10.5603/njo.96144

Bibliographic record

Nowotwory. Journal of Oncology 2023;73(5):294-302.

Keywords

leukemia
methotrexate
chemotherapy
oral mucositis

Authors

Ewa Pustelnik
Katarzyna Pikora
Katarzyna Pawelec

References (67)
  1. Wojciechowska U, Barańska K, Miklewska M, et al. Cancer incidence and mortality in Poland in 2020. Nowotwory. Journal of Oncology. 2023; 73(3): 129–145.
    CrossRef
  2. Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin. 2014; 64(2): 83–103.
    CrossRefPubMed
  3. Brigo F, Balter R, Marradi P, et al. Vincristine-related neuropathy versus acute inflammatory demyelinating polyradiculoneuropathy in children with acute lymphoblastic leukemia. J Child Neurol. 2012; 27(7): 867–874.
    CrossRefPubMed
  4. Monach PA, Arnold LM, Merkel PA. Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review. Arthritis Rheum. 2010; 62(1): 9–21.
    CrossRefPubMed
  5. Malik SW, Myers JL, DeRemee RA, et al. Lung toxicity associated with cyclophosphamide use. Two distinct patterns. Am J Respir Crit Care Med. 1996; 154(6 Pt 1): 1851–1856.
    CrossRefPubMed
  6. Campbell JM, Bateman E, Stephenson MD, et al. Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Cancer Chemother Pharmacol. 2016; 78(1): 27–39.
    CrossRefPubMed
  7. Wiczer T, Dotson E, Tuten A, et al. Evaluation of incidence and risk factors for high-dose methotrexate-induced nephrotoxicity. J Oncol Pharm Pract. 2016; 22(3): 430–436.
    CrossRefPubMed
  8. Di Francia R, Crisci S, De Monaco A, et al. Response and Toxicity to Cytarabine Therapy in Leukemia and Lymphoma: From Dose Puzzle to Pharmacogenomic Biomarkers. Cancers (Basel). 2021; 13(5).
    CrossRefPubMed
  9. Earl M. Incidence and management of asparaginase-associated adverse events in patients with acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2009; 7(9): 600–606.
    PubMed
  10. Mancilla TR, Iskra B, Aune GJ. Doxorubicin-Induced Cardiomyopathy in Children. Compr Physiol. 2019; 9(3): 905–931.
    CrossRefPubMed
  11. AIEOP-BFM ALL 2017 International collaborative treatment protocol for children and adolescents with acute lymphoblastic leukemia. A randomized phase III study conducted by the AIEOP-BFM study group. Protocol version 1.3 (date 01.02.2018).
  12. Naidu MU, Ramana GV, Rani PU, et al. Chemotherapy-induced and/or radiation therapy-induced oral mucositis--complicating the treatment of cancer. Neoplasia. 2004; 6(5): 423–431.
    CrossRefPubMed
  13. Adam de Beaumais T, Jacqz-Aigrain E. Pharmacogenetics: Applications to Pediatric Patients. Adv Pharmacol. 2018; 83: 191–215.
    CrossRefPubMed
  14. Matherly LH, Wilson MR, Hou Z. The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer. Drug Metab Dispos. 2014; 42(4): 632–649.
    CrossRefPubMed
  15. Taub JW, Ge Y. Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer. 2005; 44(1): 33–39.
    CrossRefPubMed
  16. Kroll M, Kaupat-Bleckmann K, Mörickel A, et al. Methotrexate-associated toxicity in children with Down syndrome and acute lymphoblastic leukemia during consolidation therapy with high dose methotrexate according to ALL-BFM treatment regimen. Haematologica. 2020; 105(4): 1013–1020.
    CrossRefPubMed
  17. Alaama J, Ahmad M, Ahmad S, et al. Altered Metabolism in Down Syndrome. Health Problems in Down Syndrome. 2015.
    CrossRef
  18. Sun Q, Xie Y, Zhao WH, et al. [Adverse effects of high-dose methotrexate therapy]. Zhongguo Dang Dai Er Ke Za Zhi. 2017; 19(7): 781–785.
    CrossRefPubMed
  19. Altman BJ, Stine ZE, Dang CV, et al. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer. 2016; 16(10): 619–634.
    CrossRefPubMed
  20. Tang G, Pi F, Qiu YH, et al. Postoperative parenteral glutamine supplementation improves the short-term outcomes in patients undergoing colorectal cancer surgery: A propensity score matching study. Front Nutr. 2023; 10: 1040893.
    CrossRefPubMed
  21. Gaurav K, Goel RK, Shukla M, et al. Glutamine: A novel approach to chemotherapy-induced toxicity. Indian J Med Paediatr Oncol. 2012; 33(1): 13–20.
    CrossRefPubMed
  22. Chang YH, Yu MS, Wu KH, et al. Effectiveness of Parenteral Glutamine on Methotrexate-induced Oral Mucositis in Children with Acute Lymphoblastic Leukemia. Nutr Cancer. 2017; 69(5): 746–751.
    CrossRefPubMed
  23. Widjaja NA, Pratama A, Prihaningtyas R, et al. Efficacy Oral Glutamine to Prevent Oral Mucositis and Reduce Hospital Costs During Chemotherapy in Children with Acute Lymphoblastic Leukemia. Asian Pac J Cancer Prev. 2020; 21(7): 2117–2121.
    CrossRefPubMed
  24. Coutsouvelis J, Corallo C, Spencer A, et al. A meta-analysis of palifermin efficacy for the management of oral mucositis in patients with solid tumours and haematological malignancy. Crit Rev Oncol Hematol. 2022; 172: 103606.
    CrossRefPubMed
  25. Gholizadeh N, Mehdipoor M, Sajadi H, et al. Palifermin and Chlorhexidine Mouthwashes in Prevention of Chemotherapy-Induced Mucositis in Children with Acute Lymphocytic Leukemia: a Randomized Controlled Trial. J Dent (Shiraz). 2016; 17(4): 343–347.
    PubMed
  26. Schmidt E, Thoennissen NH, Rudat A, et al. Use of palifermin for the prevention of high-dose methotrexate-induced oral mucositis. Ann Oncol. 2008; 19(9): 1644–1649.
    CrossRefPubMed
  27. Legouté F, Bensadoun RJ, Seegers V, et al. Low-level laser therapy in treatment of chemoradiotherapy-induced mucositis in head and neck cancer: results of a randomised, triple blind, multicentre phase III trial. Radiat Oncol. 2019; 14(1): 83.
    CrossRefPubMed
  28. Nunes LF, de Arruda JA, Souza AF, et al. Prophylactic photobiomodulation therapy using 660 nm diode laser for oral mucositis in paediatric patients under chemotherapy: 5-year experience from a Brazilian referral service. Lasers Med Sci. 2020; 35(8): 1857–1866.
    CrossRefPubMed
  29. de Castro JF, Abreu EG, Correia AV, et al. Low-level laser in prevention and treatment of oral mucositis in pediatric patients with acute lymphoblastic leukemia. Photomed Laser Surg. 2013; 31(12): 613–618.
    CrossRefPubMed
  30. Cruz LB, Ribeiro AS, Rech A, et al. Influence of low-energy laser in the prevention of oral mucositis in children with cancer receiving chemotherapy. Pediatr Blood Cancer. 2007; 48(4): 435–440.
    CrossRefPubMed
  31. Milstone AM, Passaretti CL, Perl TM. Chlorhexidine: expanding the armamentarium for infection control and prevention. Clin Infect Dis. 2008; 46(2): 274–281.
    CrossRefPubMed
  32. Pereira Pinto L, de Souza LB, Gordón-Núñez MA, et al. Prevention of oral lesions in children with acute lymphoblastic leukemia. Int J Pediatr Otorhinolaryngol. 2006; 70(11): 1847–1851.
    CrossRefPubMed
  33. Costa EM, Fernandes MZ, Quinder LB, et al. Evaluation of an oral preventive protocol in children with acute lymphoblastic leukemia. Pesqui Odontol Bras. 2003; 17(2): 147–150.
    CrossRefPubMed
  34. Soares AF, Aquino AR, Carvalho CH, et al. Frequency of oral mucositis and microbiological analysis in children with acute lymphoblastic leukemia treated with 0.12% chlorhexidine gluconate. Braz Dent J. 2011; 22(4): 312–316.
    CrossRefPubMed
  35. Rider B. Leucovorin. xPharm: The Comprehensive Pharmacology Reference. 2007: 1–4.
    CrossRef
  36. den Hoed MAH, Lopez-Lopez E, te Winkel ML, et al. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenomics J. 2015; 15(3): 248–254.
    CrossRefPubMed
  37. Babiak R, Campello A, Carnieri E, et al. Methotrexate: pentose cycle and oxidative stress. Cell Biochemistry and Function. 1998; 16(4): 283–293, doi: 10.1002/(sici)1099-0844(1998120)16:4<283::aid-cbf801>3.0.co;2-e.
  38. Maiguma T, Kaji H, Makino K, et al. Protective effects of amifostine and cyclooxygenase-1 inhibitor against normal human epidermal keratinocyte toxicity induced by methotrexate and 5-fluorouracil. Basic Clin Pharmacol Toxicol. 2009; 105(1): 1–9.
    CrossRefPubMed
  39. Lilleby K, Garcia P, Gooley T, et al. A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2006; 37(11): 1031–1035.
    CrossRefPubMed
  40. Aisa Y, Mori T, Kudo M, et al. Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer. 2005; 13(4): 266–269.
    CrossRefPubMed
  41. Cascinu S, Fedeli A, Fedeli SL, et al. Oral cooling (cryotherapy), an effective treatment for the prevention of 5-fluorouracil-induced stomatitis. Eur J Cancer B Oral Oncol. 1994; 30B(4): 234–236.
    CrossRefPubMed
  42. Rocke L, Loprinzi C, Lee J, et al. A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer. 1993; 72(7): 2234–2238, doi: 10.1002/1097-0142(19931001)72:7<2234::aid-cncr2820720728>3.0.co;2-n.
  43. Bruya MA, Madeira NP. Stomatitis after chemotherapy. Am J Nurs. 1975; 75(8): 1349–1352.
    PubMed
  44. World Health Organization: WHO Offset Publication. World Health Organization (1979).
  45. Reyad FA, Elsayed NM, El Chazli Y. Photobiomodulation for chemotherapy-induced oral mucositis in leukemic children: A randomized controlled clinical trial. Oral Dis. 2023; 29(5): 2239–2247.
    CrossRefPubMed
  46. Kuhn A, Porto FA, Miraglia P, et al. Low-level infrared laser therapy in chemotherapy-induced oral mucositis: a randomized placebo-controlled trial in children. J Pediatr Hematol Oncol. 2009; 31(1): 33–37.
    CrossRefPubMed
  47. Cauwels RG, Martens LC. Low level laser therapy in oral mucositis: a pilot study. Eur Arch Paediatr Dent. 2011; 12(2): 118–123.
    CrossRefPubMed
  48. Karaman K, Sarica A, Tunc SK, et al. Is Low-level Laser Therapy a Candidate to Be a Good Alternative in the Treatment of Mucositis in Childhood Leukemia? J Pediatr Hematol Oncol. 2022; 44(1): e199–e203.
    CrossRefPubMed
  49. Fiwek P, Emerich K, Irga-Jaworska N, et al. Photobiomodulation Treatment in Chemotherapy-Induced Oral Mucositis in Young Haematological Patients-A Pilot Study. Medicina (Kaunas). 2022; 58(8).
    CrossRefPubMed
  50. Ban Y, Yang X, Xing Y, et al. Intrauterine Infusion of Leukocyte-Poor Platelet-Rich Plasma Is an Effective Therapeutic Protocol for Patients with Recurrent Implantation Failure: A Retrospective Cohort Study. J Clin Med. 2023; 12(8).
    CrossRefPubMed
  51. Sriram S, Hasan S, Alqarni A, et al. Efficacy of Platelet-Rich Plasma Therapy in Oral Lichen Planus: A Systematic Review. Medicina (Kaunas). 2023; 59(4).
    CrossRefPubMed
  52. Piccin A, Di Pierro AM, Canzian L, et al. Platelet gel: a new therapeutic tool with great potential. Blood Transfus. 2017; 15(4): 333–340.
    CrossRefPubMed
  53. Piccin A, Rebulla P, Pupella S, et al. Impressive tissue regeneration of severe oral mucositis post stem cell transplantation using cord blood platelet gel. Transfusion. 2017; 57(9): 2220–2224.
    CrossRefPubMed
  54. Aielli F, Giusti R, Rughetti A, et al. Rapid resolution of refractory chemotherapy-induced oral mucositis with platelet gel-released supernatant in a pediatric cancer patient: a case report. J Pain Symptom Manage. 2014; 48(5): e2–e4.
    CrossRefPubMed
  55. Picardi A, Ferraro AS, Miranda M, et al. Therapeutic efficiency of platelet gel for the treatment of oral ulcers related to chronic graft versus host disease after allogeneic haematopoietic stem cell transplantation. Oral Implantol (Rome). 2017; 10(4): 398–405.
    CrossRefPubMed
  56. Albrecht K, Łaguna P, Lachert E, et al. Efficacy of Platelet Gel in Children with Stomatitis during Chemotherapy. Postepy Hig Med Dosw. 2021; 75(1): 720–723.
    CrossRef
  57. Althunibat OY, Abukhalil MH, Jghef MM, et al. Hepatoprotective effect of taxifolin on cyclophosphamide-induced oxidative stress, inflammation, and apoptosis in mice: Involvement of Nrf2/HO-1 signaling. Biomol Biomed. 2023; 23(4): 649–660.
    CrossRefPubMed
  58. Alaswad HA, Mahbub AA, Le Maitre CL, et al. Molecular Action of Polyphenols in Leukaemia and Their Therapeutic Potential. Int J Mol Sci. 2021; 22(6).
    CrossRefPubMed
  59. Bayramoglu Z, Mokhtare B, Mendil AS, et al. Effect of taxifolin on methotrexate-induced oxidative and inflammatory oral mucositis in rats: biochemical and histopathological evaluation. J Appl Oral Sci. 2022; 30: e20220115.
    CrossRefPubMed
  60. Loprinzi CL, Ghosh C, Camoriano J, et al. Phase III controlled evaluation of sucralfate to alleviate stomatitis in patients receiving fluorouracil-based chemotherapy. J Clin Oncol. 1997; 15(3): 1235–1238.
    CrossRefPubMed
  61. LeVeque FG, Parzuchowski JB, Farinacci GC, et al. Clinical evaluation of MGI 209, an anesthetic, film-forming agent for relief from painful oral ulcers associated with chemotherapy. J Clin Oncol. 1992; 10(12): 1963–1968.
    CrossRefPubMed
  62. Saunders DP, Rouleau T, Cheng K, et al. Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients and clinical practice guidelines. Support Care Cancer. 2020; 28(5): 2473–2484.
    CrossRefPubMed
  63. Sarvizadeh M, Hemati S, Meidani M, et al. Morphine mouthwash for the management of oral mucositis in patients with head and neck cancer. Adv Biomed Res. 2015; 4: 44.
    CrossRefPubMed
  64. Nicolatou-Galitis O, Bossi P, Orlandi E, et al. The role of benzydamine in prevention and treatment of chemoradiotherapy-induced mucositis. Support Care Cancer. 2021; 29(10): 5701–5709.
    CrossRefPubMed
  65. Epstein J, Silverman S, Paggiarino D, et al. Benzydamine HCl for prophylaxis of radiation-induced oral mucositis. Cancer. 2001; 92(4): 875–885, doi: 10.1002/1097-0142(20010815)92:4<875::aid-cncr1396>3.0.co;2-1.
  66. Comparcini D, Simonetti V, Galli F, et al. Immersive and Non-Immersive Virtual Reality for Pain and Anxiety Management in Pediatric Patients with Hematological or Solid Cancer: A Systematic Review. Cancers (Basel). 2023; 15(3).
    CrossRefPubMed
  67. Hoffman HG, Richards TL, Van Oostrom T, et al. The analgesic effects of opioids and immersive virtual reality distraction: evidence from subjective and functional brain imaging assessments. Anesth Analg. 2007; 105(6): 1776–83, table of contents.
    CrossRefPubMed

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