Capecitabine-induced hand foot syndrome: a brief look at possible pathways that may be associated with inflammation

Abstract

Hand foot syndrome is a toxic reaction related to certain chemotherapy agents. Capecitabine is a prodrug used in the treatment of many cancers, such as gastrointestinal, biliary tract and breast cancers. It is associated with hand and foot syndrome (HFS), which preferentially affects palms and soles. There is still no consensus on effective international standard therapeutic strategies for the treatment and prevention of HFS because the underlying physiological and pharmacological mechanisms leading to the development of HFS have not been adequately explained. HFS is rarely life-threatening, but it may deteriorate the patient’s quality of life. Quitting or a reduction in the dose of the causative drug mostly provide the amelioration of the symptoms. The aim of this review is to briefly evaluate the possible inflammatory mechanisms that may be associated with capecitabine- induced HFS.

Keywords

• Capecitabine
• Hand foot syndrome
• Cyclooxygenase 2

Kapesitabine bağlı el ayak sendromu: enflamasyonla ilişkili olabilecek olası yolaklara kısa bir bakış

Abstract

El ayak sendromu, belirli bazı kemoterapi ajanlarıyla ilişkili toksik bir reaksiyondur. Kapesitabin, gastrointestinal sistem, safra yolları ve meme kanserleri gibi birçok kanserin tedavisinde kullanılan bir ön ilaçtır. Tercihen avuç içi ve ayak tabanlarını etkileyen el ve ayak sendromu (HFS) ile ilişkilidir. HFS gelişimine yol açan altta yatan fizyolojik ve farmakolojik mekanizmalar yeterince açıklanamadığından, HFS'nin tedavisi ve önlenmesi için etkili uluslararası standart tedavi edici stratejiler üzerinde hala bir görüş birliği yoktur. HFS nadiren yaşamı tehdit eder, ancak hastanın yaşam kalitesini bozabilir. Sebep olan ilacın bırakılması veya dozunun azaltılması çoğunlukla semptomların düzelmesini sağlar. Bu derlemenin amacı, kapesitabin ile indüklenen HFS ile ilişkili olabilecek olası enflamatuvar mekanizmaları kısaca değerlendirmektir.

Keywords

• Kapesitabin
• El ayak sendromu
• siklooksijenaz-2

References

1. 1Nagore E, Insa A, Sanmartín O. Antineoplastic therapy-induced palmar plantar erythrodysesthesia ('hand-foot') syndrome. Incidence, recognition and management. Am J Clin Dermatol. 2000 ;1(4):225-34. doi: 10.2165/00128071-200001040-00004.
2. Burgdorf WH, Gilmore WA, Ganick RG. Peculiar acral erythema secondary to high-dose chemotherapy for acute myelogenous leukemia. Ann Intern Med. 1982;97(1):61-2. doi: 10.7326/0003-4819-97-1-61.
3. Zuehlke RL. Erythematous eruption of the palms and soles associated with mitotane therapy. Dermatologica. 1974;148(2):90-2. doi: 10.1159/000251603.
4. Baack BR, Burgdorf WH. Chemotherapy-induced acral erythema. J Am Acad Dermatol. 1991;24(3):457-61. doi: 10.1016/0190-9622(91)70073-b.
5. Lassere Y, Hoff P. Management of hand-foot syndrome in patients treated with capecitabine (Xeloda). Eur J Oncol Nurs. 2004;8 Suppl 1:S31-40. doi: 10.1016/j.ejon.2004.06.007.
6. Gressett SM, Stanford BL, Hardwicke F. Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract. 2006 ;12(3):131-41. doi: 10.1177/1078155206069242.
7. Lipworth AD, Robert C, Zhu AX. Hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia): focus on sorafenib and sunitinib. Oncology. 2009;77(5):257-71. doi: 10.1159/000258880.
8. Degen A, Alter M, Schenck F, Satzger I, Völker B, Kapp A, et al. The hand-foot-syndrome associated with medical tumor therapy - classification and management. J Dtsch Dermatol Ges. 2010 ;8(9):652-61. English, German. doi: 10.1111/j.1610-0387.2010.07449.x.

9. Saif MW. Capecitabine and hand-foot syndrome. Expert Opin Drug Saf. 2011 ;10(2):159-69. doi: 10.1517/14740338.2011.546342.
10. Miller KK, Gorcey L, McLellan BN. Chemotherapy-induced hand-foot syndrome and nail changes: a review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol. 2014 ;71(4):787-94. doi: 10.1016/j.jaad.2014.03.019.
11. Kwakman JJM, Elshot YS, Punt CJA, Koopman M. Management of cytotoxic chemotherapy-induced hand-foot syndrome. Oncol Rev. 2020 ;14(1):442. doi: 10.4081/oncol.2020.442.
12. Pandy JGP, Franco PIG, Li RK. Prophylactic strategies for hand-foot syndrome/skin reaction associated with systemic cancer treatment: a meta-analysis of randomized controlled trials. Support Care Cancer. 2022 ; 30(11):8655-8666. doi: 10.1007/s00520-022-07175-3.
13. Urakawa R, Tarutani M, Kubota K, Uejima E. Hand Foot Syndrome Has the Strongest Impact on QOL in Skin Toxicities of Chemotherapy. J Cancer. 2019 ;10(20):4846-4851. doi: 10.7150/jca.31059.
14. de Queiroz MVR, de Medeiros ACTR, Toledo SP, de Abreu Sarmenghi KD, de Vasconcellos VF. Hand-foot syndrome caused by capecitabine: incidence, risk factors and the role of dermatological evaluation. Ecancermedicalscience. 2022;16:1390. doi: 10.3332/ecancer.2022.1390
15. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (CTCAEv5.0) [Internet]. [cited 2024 Jan 28]. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm
16. Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol. 1999;17(2):485-93. doi: 10.1200/JCO.1999.17.2.485.
17. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol. 2003 ;13(3):176-81. doi: 10.1016/S1053-4296(03)00031-6.
18. Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005;27(1):23-44. doi: 10.1016/j.clinthera.2005.01.005.
19. Roche Laboratories, Xeloda(R) (capecitabine): Highlights of prescribing information. 2022. U.S. Food and Drug Administration website [Internet]. [cited 2024 Jan 28]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/020896s044s045s046s047s048s049s050s051lbl.pdf
20. Charalambous A, Tsitsi T, Astras G, Paikousis L, Filippou E. A pilot randomized double-blind, placebo-controlled study on the effects of the topical application of pyridoxine on palmar-plantar erythrodysesthesia (PPE) induced by capecitabine or pegylated liposomal doxorubicin (PLD). Eur J Oncol Nurs. 2021;50:101866. doi: 10.1016/j.ejon.2020.101866.
21. Fariña MC, Andrade J, Soriano ML, et al. Eritema acral inducido por quimioterapia. Descripción de cuatro casos y revisión de la literatura. Actas Dermosifiliogr 1998; 89: 385-91
22. Lokich JJ, Moore C. Chemotherapy-associated palmar-plantar erythrodysesthesia syndrome. Ann Intern Med. 1984 ;101(6):798-9. doi: 10.7326/0003-4819-101-6-798.
23. Vogelzang NJ, Ratain MJ. Cancer chemotherapy and skin changes. Ann Intern Med. 1985 ;103(2):303-4. doi: 10.7326/0003-4819-103-2-303_3.
24. Chiara S, Nobile MT, Barzacchi C, Sanguineti O, Vincenti M, Di Somma C, et al. Hand-foot syndrome induced by high-dose, short-term, continuous 5-fluorouracil infusion. Eur J Cancer. 1997 ;33(6):967-9. doi: 10.1016/s0959-8049(96)00497-2.
25. Nishijima TF, Suzuki M, Muss HB. A comparison of toxicity profiles between the lower and standard dose capecitabine in breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat. 2016;156(2):227-36. doi: 10.1007/s10549-016-3756-5.
26. Abushullaih S, Saad ED, Munsell M, Hoff PM. Incidence and severity of hand-foot syndrome in colorectal cancer patients treated with capecitabine: a single-institution experience. Cancer Invest. 2002;20(1):3-10. doi: 10.1081/cnv-120000360.
27. Jucgla A, Sais G. Diagnosis in oncology. Hand-foot syndrome. J Clin Oncol. 1997 ;15(9):3164. doi: 10.1200/JCO.1997.15.9.3164.
28. Wong M, Choo SP, Tan EH. Travel warning with capecitabine. Ann Oncol. 2009 ;20(7):1281. doi: 10.1093/annonc/mdp278.
29. Macedo LT, Lima JP, dos Santos LV, Sasse AD. Prevention strategies for chemotherapy-induced hand-foot syndrome: a systematic review and meta-analysis of prospective randomised trials. Support Care Cancer. 2014 ;22(6):1585-93. doi: 10.1007/s00520-014-2129-z.
30. Chantharakhit C, Sujaritvanichpong N. Predictive factors for the development of capecitabine-induced hand-foot syndrome: a retrospective observational cohort study. Ann Med Surg (Lond). 2023 ;86(1):73-77. doi: 10.1097/MS9.0000000000001487.
31. Lou Y, Wang Q, Zheng J, Hu H, Liu L, Hong D, et al. Possible Pathways of Capecitabine-Induced Hand-Foot Syndrome. Chem Res Toxicol. 2016 ;29(10):1591-1601. doi: 10.1021/acs.chemrestox.6b00215.
32. Beard JS, Smith KJ, Skelton HG. Combination chemotherapy with 5-fluorouracil, folinic acid, and alpha-interferon producing histologic features of graft-versus-host disease. J Am Acad Dermatol. 1993;29(2 Pt 2):325-30. doi: 10.1016/0190-9622(93)70187-x.
33. Valks R, Fraga J, Porras-Luque J, Figuera A, Garcia-Diéz A, Fernändez-Herrera J. Chemotherapy-induced eccrine squamous syringometaplasia. A distinctive eruption in patients receiving hematopoietic progenitor cells. Arch Dermatol. 1997;133(7):873-8. doi:10.1001/archderm.1997.03890430089012
34. Horn TD. Antineoplastic Chemotherapy, Sweat, and the Skin. Arch Dermatol. 1997;133(7):905–906. doi:10.1001/archderm.1997.03890430123017
35. Asgari MM, Haggerty JG, McNiff JM, Milstone LM, Schwartz PM. Expression and localization of thymidine phosphorylase/platelet-derived endothelial cell growth factor in skin and cutaneous tumors. J Cutan Pathol. 1999;26(6):287-94. doi: 10.1111/j.1600-0560.1999.tb01846.x.
36. Milano G, Etienne-Grimaldi MC, Mari M, Lassalle S, Formento JL, Francoual M, et al. Candidate mechanisms for capecitabine-related hand-foot syndrome. Br J Clin Pharmacol. 2008 ;66(1):88-95. doi: 10.1111/j.1365-2125.2008.03159.x
37. Yen-Revollo JL, Goldberg RM, McLeod HL. Can inhibiting dihydropyrimidine dehydrogenase limit hand-foot syndrome caused by fluoropyrimidines? Clin Cancer Res. 2008;14(1):8-13. doi: 10.1158/1078-0432.CCR-07-1225.
38. Saif MW, Elfiky A, Diasio R. Hand-foot syndrome variant in a dihydropyrimidine dehydrogenase-deficient patient treated with capecitabine. Clin Colorectal Cancer. 2006 ;6(3):219-23. doi: 10.3816/CCC.2006.n.039.
39. Lou Y, Wang Q, Zheng J, Wang X, Jiang W, Zheng Y, et al. Identification of the Novel Capecitabine Metabolites in Capecitabine-Treated Patients with Hand-Foot Syndrome. Chem Res Toxicol. 2018;31(10):1069-1079. doi: 10.1021/acs.chemrestox.8b00150.
40. Cianchi F, Cortesini C, Bechi P, Fantappiè O, Messerini L, Vannacci A, et al. Up-regulation of cyclooxygenase 2 gene expression correlates with tumor angiogenesis in human colorectal cancer. Gastroenterology. 2001;121(6):1339-47. doi: 10.1053/gast.2001.29691.
41. Lin E, Morris JS, Ayers GD. Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity. Oncology (Williston Park). 2002 ;16(12 Suppl No 14):31-7.
42. Lin EH, Curley SA, Crane CC, Feig B, Skibber J, Delcos M, et al. Retrospective study of capecitabine and celecoxib in metastatic colorectal cancer: potential benefits and COX-2 as the common mediator in pain, toxicities and survival? Am J Clin Oncol. 2006;29(3):232-9. doi: 10.1097/01.coc.0000217818.07962.67.
43. Zhang RX, Wu XJ, Wan DS, Lu ZH, Kong LH, Pan ZZ, et al. Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: result of a single-center, prospective randomized phase III trial. Ann Oncol. 2012 May;23(5):1348-1353. doi: 10.1093/annonc/mdr400.
44. Huang XZ, Chen Y, Chen WJ, Zhang X, Wu CC, Wang ZN, et al. Clinical evidence of prevention strategies for capecitabine-induced hand-foot syndrome. Int J Cancer. 2018 ;142(12):2567-2577. doi: 10.1002/ijc.31269.
45. Shayeganmehr D, Ramezannia F, Gharib B, Rezaeilaal A, Shahi F, Jafariazar Z, et al. Pharmaceutical and clinical studies of celecoxib topical hydrogel for management of chemotherapy-induced hand-foot syndrome. Naunyn Schmiedebergs Arch Pharmacol. 2023;396(7):1571-1581. doi: 10.1007/s00210-022-02339-8.
46. Santhosh A, Sharma A, Bakhshi S, Kumar A, Sharma V, Malik PS, et al. D-TORCH Trial Investigators. Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial. J Clin Oncol. 2024:JCO2301730. doi: 10.1200/JCO.23.01730.
47. Deng Y, Yao H, Chen W, Wei H, Li X, Zhang F, et al. Profiling of polar urine metabolite extracts from Chinese colorectal cancer patients to screen for potential diagnostic and adverse-effect biomarkers. J Cancer. 2020 ;11(23):6925-6938. doi: 10.7150/jca.47631.
48. Chen M, Chen J, Peng X, Xu Z, Shao J, Zhu Y, et al. The contribution of keratinocytes in capecitabine-stimulated hand-foot-syndrome. Environ Toxicol Pharmacol. 2017;49:81-88. doi: 10.1016/j.etap.2016.12.001
49. He X, Wang J, Wang Q, Liu J, Yang X, He L, et al. P38 MAPK, NF-κB, and JAK-STAT3 Signaling Pathways Involved in Capecitabine-Induced Hand-Foot Syndrome via Interleukin 6 or Interleukin 8 Abnormal Expression. Chem Res Toxicol. 2022 ;35(3):422-430. doi: 10.1021/acs.chemrestox.1c00317.
50. Yang B, Xie X, Lv D, Hu J, Chen Y, Wu Z, et al. Capecitabine induces hand-foot syndrome through elevated thymidine phosphorylase-mediated locoregional toxicity and GSDME-driven pyroptosis that can be relieved by tipiracil. Br J Cancer. 2023 ;128(2):219-231. doi: 10.1038/s41416-022-02039-3