Growth Factors and Effects of Palifermin in Management of Cancer Therapy Induced Oral Mucositis

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Noopur Shrivastava, MDS


Amongst the various hazards of chemotherapeutic drugs and radiation in cancer patients, oral mucositis is the most commonly encountered and troublesome complication so far. It can be a cause for discontinuation of therapy and may add to the cost of treatment. In this article, pathogenesis of oral mucositis and role of recombinant human growth factors in management of it  have been discussed, as we need to achieve a guideline for proper treatment of this painful side effect of cancer treatment. Palifermin, a keratinocyte growth factor has been shown to give promising results in cases of severe mucositis in hematopoetic stem cell transplant patients undergoing combined chemoradiotherapy. Other exogenous growth factors are also effective in the management of mucositis when administered topically or subcutaneously, but there is need for more number of studies with a large sample size for establishing a proper treatment plan which is cost effective as well as helpful in reducing patient’s discomfort.


Keywords: Chemotherapy, Radiotherapy, Growth factors, Oral Mucositis, Hematopoietic stem cell transplant.

Keywords: Chemotherapy, Radiotherapy, Growth factors, Oral Mucositis, Hematopoietic stem cell transplant

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SHRIVASTAVA, Noopur. Growth Factors and Effects of Palifermin in Management of Cancer Therapy Induced Oral Mucositis. Medical Research Archives, [S.l.], v. 10, n. 11, nov. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 17 june 2024. doi:
Research Articles


1. Shrivastava N. Targeted management of cancer therapy induced oral mucositis. J of Advanced Health Sciences and Research. 2021; 2(1): 90-101.
2. Rzepecki P, Oborska S, Wasko-Grabowska A, Mlot B, Barzal J. Pharmacotherapy of oral mucositis with Palifermin. Clinical Medicine: Therapeutics. 2009;1: 333-342.
3. Rodriguez- Caballero A, Torres- Lagares D, Robles- Garcia M, Pachon- Ibanez J, Gonzalez- Padilla D, Gutierrez- Perez JL. Cancer treatment- induced oral mucositis: a critical review. Int J Oral Maxillofac Surg. 2012; 41(2): 225-238.
4. Epstein JB, Gorsky M, Guglietta A, Le N, Sonis ST. The correlation between epidermal growth factor levels in saliva and the severity of oral mucositis during oropharyngeal radiation therapy. Cancer.2000; 89 (11): 2258-2265.
5. Girdler NM, McGurk M, Aqual S, Prince M. The effect of epidermal growth factor mouthwash on cytotoxic- induced oral ulceration. A Phase I clinical trial. Am J Clin Oncol. 1995; 18: 403-6.
6. Epstein JB, Emerton S, Guglietta A, Le N. Assessment of epidermal growth factor in oral secretions of patients receiving radiation therapy for cancer. Oral Oncol. 1997; 33: 359-63.
7. Sonis ST, Costa JW Jr., Evitts SM, Lindquist LE, Nicolson M. Effect of epidermal growth factor on ulcerative mucositis in hamsters that receive cancer chemotherapy. Oral Surg Oral Med Oral Pathol. 1992; 74: 749-55.
8. Hong JP, Lee SW, Song SY, Ahn SD, Shin SS, Choi EK, Kim JH. Recombinant human epidermal growth factor treatment of radiation- induced severe oral mucositis in patients with head and neck malignancies. European Journal of Cancer Care. 2009; 18: 636-41.
9. Kim KI, Kim JW, Lee HJ, Kim BS, Bang SM, Kim I et al. Recombinant human epidermal growth factor on oral mucositis induced by intensive chemotherapy with stem cell transplantation. Am J Hematol. 2013; 88: 107-112.
10. Kim JW, Kim MG, Lee HJ, Koh Y, Kwon JH, Kim I et al. Topical recombinant human epidermal growth factor for oral mucositis induced by intensive chemotherapy with hematopoietic stem cell transplantation: Final analysis of a randomized, double- blind, placebo- controlled, phase 2 trial. 2017; doi:10.1371/ journal. pone. 0168854.
11. Barnes DW. Epidermal growth factor inhibits growth of A431 human epidermoid carcinoma in serum- free cell culture. Journal of Cell Biology. 1982; 83: 1-4.
12. Christen RD, Hom DK, Porter DC, Andrews PA, MacLeod CL, Hafstrom L, Howell SB. Epidermal growth factor regulates the in vitro sensitivity of human ovarian carcinoma cells to cisplatin. Journal of Clinical Investigation. 1990; 86: 1632-1640.
13. Gill GN, Lazar CS. Increased phosphotyrosine content and inhibition of proliferation in EGF- treated A431 cells. Nature. 1981; 293: 305-307.
14. Kamata N, Chida K, Rikimaru K, Horikoshi M, Enomoto S, Kuroki T. Growth- inhibitory effects of epidermal growth factor and overexpression of its receptors on human squamous cell carcinoma in culture. Cancer Research. 1986; 46: 1648-1653.
15. Choi J, Moon SY, Hong JP et al. Epidermal growth factor induces cell death in the absence of overexpressed epidermal growth factor receptor and ErbB2 in various human cancer cell lines. Cancer Invest. 2010; 28: 505-514.
16. Ryu SH, Kang KM, Moon SY, Chai GY, Hong JP, Cho KO et al. Therapeutic effects of recombinant human epidermal growth factor (rh EGF) in a murine model of concurrent chemo and radiotherapy- induced oral mucositis. J Radiat Res. 2010; 51: 595-601.
17. Logan RM, Al- Azri AR, Bossi P et al. Systematic review of growth factors and cytokines for the management of oral mucositis in cancer patients and clinical practice guidelines. Supportive Care in Cancer. 2020; 28: 2485-2498.
18. Rovirosa A, Ferre J, Biete A. Granulocyte macrophage colony stimulating factor mouthwashes heal oral ulcers during head and neck radiotherapy. Int J Radiation Oncology Biol Phys. 1998; 41(4): 747-754.
19. Karthaus M, Rosenthal C, Huebner G et al. Effect of topical oral G-CSF on oral mucositis: a randomized placebo controlled trial. Bone Marrow Transplantation. 1998; 22: 781-785.
20. Gabrilove JL, Jakubowski A, Scher H et al. Effect of granulocyte colony stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional cell carcinoma of the urothelium. N Engl J Med. 1988; 318: 1414-1422.
21. Fleetwood AJ, Cook AD, Hamilton JA. Functions of granulocyte macrophage colony- stimulating factor. Crit Rev Immunol. 2005; 25: 405-428.
22. Hamilton JA. GM- CSF in inflammation and auroimmunity. Trends Immunol. 2002; 23: 403-408.
23. Gutschalk CM, Herold- Mende CC, Fusenig NE, Mueller MM. Granulocyte colony- stimulating factor and granulocyte- macrophage colony stimulating factor promote malignant growth of cells from head and neck squamous cell carcinoma in vivo. Cancer Res. 2006; 66(16): 8026-8035.
24. Chi KH, Chen CH, Chan WK et al. Effect of granulocyte- macrophage colony- stimulating factor on oral mucositis in head and neck cancer patients after cisplatin, fluorouracil, and leucovorin chemotherapy. Journal of Clinical Oncology. 1995; 13(10): 2620-2628.
25. Zaghloul MS, Dorie MJ, Kallman RF. Interleukin 1 increase thymidine labeling index of normal tissue of mice but not the tumor. Int J Radiat Oncol Biol Phys. 1994; 29: 805-811.
26. Neumanaitis J, Rosenfeld CS, Ash R et al. Phase III randomized double- blind, placebo- controlled trial of rhGM-CSF following allogenic bone marrow transplantation. Bone Marrow Transplant. 1995; 15: 949-954.
27. Masucci G, Fernberg JO, Hoglun Ersin L, Lewensohn R, Strader H. Beneficial treatment of radiotherapy induced mucositis with rh-GM-CSF in patients with tumors of the oral cavity/ oropharynx. Sixth International Congress on Anticancer Treatment. 1996; 167: 83.
28. Throuvalas N, Antonadou D, Pullizi M, Sarris G. Evaluation of efficacy and safety of GM- CSF in the prophylaxis of mucositis in patients with head and neck cancer treated with RT. Eur J Cancer. 1997;41A:431.
29. Crawford J, Ozer H, Stoller R et al. Reduction by granulocyte colony stimulating factor of fever and neutropenia induced by chemotherapy in patients with small cell lung cancer. N Engl J Med. 1991; 325: 164-170.
30. Crawford J, Glaspy J, Vincent M et al. Effect of Filgrastim (r-metHuG- CSF) on oral mucositis in patients with small cell lung cancer receiving chemotherapy cyclophosphamide, doxorubicin and etoposide. Proc Am Soc Clin Oncol. 1994; 13: 331.
31. Gordon B, Spadinger A, Hodges E et al. Effect of granulocyte macrophage colony stimulating factor on oral mucositis after hematopoietic stem-cell transplantation. J Clin Oncol. 1994; 12: 1917-1922.
32. Kannan V, Bapsy PP, Anantha N, Doval DC et al. Efficacy and safety of granulocyte macrophage colony stimulating factor (GM-CSF) on the frequency and severity of radiation mucositis in patients with head and neck carcinoma. Int J Radiat Oncol Biol Phys. 1997; 37: 1005-1010.
33. De la Torre A, Regueiro CA, Valcarcel FJ. Granulocyte macrophage colony stimulating factor mouthwashes improve radiation induced mucositis in AIDS patients. Radiother Oncol. 1997; 43: 229-230.
34. Meropol NJ, Miller LL, Korn EL et al. Severe myelosuppression resulting from concurrent administration of granulocyte colony stimulating factor and cytotoxic chemotherapy. J Natl Cancer Inst. 1992; 84: 1201-1203.
35. Grem JL, McAtee N, Murphy RF et al. Phase I and pharmacokinetic study of recombinant human granulocyte- macrophage colony stimulating factor given in combination with fluorouracil plus calcium leucovorin in metastatic gastrointestinal adenocarcinoma. J clin Oncol. 1994;12: 560-568.
36. Sonis ST, Costa JW Jr, Evitts SM et al. Effect of epidermoid growth factor on ulcerative mucositis in hamsters that receive chemotherapy. Oral Surg Oral Med Oral Pathol. 1992; 74: 749-755.
37. Sonis ST, Lindquist L, Vugt V et al. Prevention of chemotherapy induced ulcerative mucositis by transforming growth factor β3. Cancer Res. 1994; 54: 1135-1138.
38. Withers HR, Taylor JMG, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol. 1988; 27: 131-146.
39. Tannock IF. Combined modality treatment with radiotherapy and chemotherapy. Radiother Oncol. 1989; 16: 83-101.
40. Dorr W, Kummermehr J. Accelerated repopulation of mouse tongue epithelium during fractionated irradiations or following single doses. Radiother Oncol. 1990; 17: 249-259.
41. Maclejewski B, Zajusz A, Pilecki B et al. Escalated hyperfractionation and stimulation of acute mucosal reaction in radiotherapy for cancer of the oral cavity and oropharynx. Semin Radiat Oncol. 1992; 2: 54-57.
42. Sprinzl G, Galvan O, De Vries A, Ulmer H et al. Local application of granulocyte- macrophage colony stimulating factor (GM- CSF) for the treatment of oral mucositis. European Journal of Cancer. 2001; 37(16): 2003-9.
43. Bian L, Han G, Zhao CW, Gari PJ, Wang XJ. The role of Smad7 in oral mucositis. Protein cell. 2015; 6(3): 160-169.
44. Han G, Li F, Ten DP, Wang XJ. Temporal Smad7 transgene induction in mouse epidermis accelerates skin wound healing. Am J Pathol. 2011; 179: 1768-1779.
45. Han G, Bian J, Li F et al. Preventive and therapeutic affects of Smad7 on radiation- induced oral mucositis. Nat Med. 2013; 19: 421-428.
46. Boss MK, Ke Y, Bian L et al. Therapeutic intervention using a Smad7- based Tat protein to treat radiation- induced oral mucositis. International Journal of Radiation Oncology Biology Physics. 2022; 112(3): 759-770.
47. Shull MM et al. Targeted disruption of the mouse transforming growth factor- beta 1 gene results in multifocal inflammatory disease. Nature. 1992; 359: 693-699.
48. Kulkarni AB et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA. 1993; 90: 770-774.
49. Pasparakis M et al. TNF mediated inflammatory skin disease in mice with epidermis- specific deletion of IKK2. Nature. 2002; 417: 861-866.
50. Akhurst RJ, Hata A. Targeting the TGF beta signaling pathway in disease. Nature Reviews Drug Discovery. 2012;11: 790-811.
51. Wu S, Zhang Y, Xu L, Dai Y, Ma S et al. Multicenter randomized study of genetically modified recombinant Human interleukin-11 to prevent chemotherapy- induced thrombocytopenia in cancer patients receiving chemotherapy. Support Care Cancer. 2012; 20(8): 1875-84.
52. Liu Z, Wang Y, Yan J, Liu J et al. Efficacy and safety of recombinant human interleukin-11 in the treatment of acute leukaemia patients with chemotherapy- induced thrombocytopenia: a systematic review and meta- analysis. J Eval Clin Pract. 2020; 26(1): 262-71.
53. Lopez- Gonzalez A, Garcia- Quintanilla M, Guerrero- Agenjo CM, Tendero JL, Guisado- Requena LM, Rabanales- Sotos J. Efficacy of cryotherapy in the prevention of oral mucositis in adult patients with chemotherapy. Int J Environ Res Public Health. 2021; 18(3): 994.
54. Antin J, Lee SJ, Neuberg D, Alyea E, Soiffer RJ, Sonis S et al. A phase I/II double- blind, placebo- controlled study of recombinant human interleukin-11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation. Bone Marrow Transplant. 2002; 29(5):373-7.
55. Wei H, Wei J, Dong X. A prospective interventional study of recombinant human interleukin-11 mouthwash in chemotherapy- induced oral mucositis. BMC Oral Health. 2022; 22: 313.
56. Sonis S, Edwards L, Lucey C. The biological basis for the attenuation of mucositis: the example of interleukin-11. Leukemia. 1999; 13: 831-34.
57. Villa A, Sonis ST. Mucositis: pathobiology and management. Curr Opin Oncol. 2015; 27(3): 159-64.
58. Sonis S, Muska A, O’Brien J, Van Vugt A, Langer- Safer P, Keith J. Alteration in frequency, severity and duration of chemotherapy- induced mucositis in hamsters by interleukin-11. Oral Oncol Eur J Cancer. 1995; 31B: 261-266.
59. Barasch A, Epstein J, Tilashalski K. Palifermin for management of treatment- induced oral mucositis in cancer patients. Biologics: Targets & Therapy. 2009; 3: 111-116.
60. Vadhan- Raj S, Goldberg JD, Perales MA, Berger DP, Brink MRM. Clinical applications of palifermin: amelioration of oral mucositis and other potential indications. J Cell Mol Med. 2013; 17(11): 1371-1384.
61. Sonis ST. Efficacy of palifermin (keratinocyte growth factor-1) in amelioration of oral mucositis. Core Evidence. 2009; 4: 199-205.
62. McKeown ST, Hyland PL, Locke M, Mackenzie IC, Irwin CR. Keratinocyte growth factor and scatter factor expression by regionally defined oral fibroblasts. Eur J Oral Sci. 2003; 111: 42-50.
63. Jeschke MG, Richter G, Hofstadter F, Herndon DN, Perez-Polo JR, Jaunch KW. Non-viral liposomal Keratinocyte growth factor (KGF) cDNA gene transfer improves dermal and epidermal regeneration through stimulation of epithelial and mesenchymal factors. Gene Ther. 2002; 9: 1065-1074.
64. Finch PW, Rubin JS. Keratinocyte growth factor/ fibroblast growth factor 7, a homeostatic factor with therapeutic potential for epithelial protection and repair. Adv Cancer Res. 2004; 91: 69-136.
65. Blijlevens N, Sonis S. Palifermin (recombinant keratinocyte growth factor-1): a pleiotropic growth factor with multiple biological activities in preventing chemotherapy and radiotherapy- induced mucositis. Ann Oncol. 2007; 18: 817-26.
66. Oronsky B, Goyal S, Kim MM et al. A review of clinical radioprotection and chemoprotection for oral mucositis. Translational Oncology. 2018; 11: 771-778.
67. Keijzer A, Huijgens PC, Van De Loosdrecht AA. Palifermin and palmar- plantar erythrodysesthesia. Br J Haematol. 2007; 136: 856-857.
68. Milne O, Cutts B, LcLean C et al. Palifermin- induced acral erythrodysaesthesia variant in the treatment of acute myeloid leukaemia. Australas J Dermatol. 2011; 52: 59-61.
69. Mozaffari HR, Payandeh M, Ramezani M, Sadeghi M, Mahmoudiahmadabadi M, Sharifi R. Efficacy of palifermin on oral mucositis and acute GVHD after hematopoietic stem cell transplantation (HSCT) in hematology malignancy patients: a meta- analysis of trials.
70. Farrell CL, Rex KL, Kaufman SA et al. Effects of keratinocyte growth factor in the squamous epithelium of the upper aerodigestive tract of normal and irradiated mice. Int J Radiat Biol. 1999; 75: 609-620.
71. Potten CS, Booth D, Cragg NJ et al. Cell kinetic studies in the murine ventral tongue epithelium: mucositis induced by radiation and its protection by pretreatment with keratinocyte growth factor (KGF). Cell Prolif. 2002; 35(suppl 1): 32-47.
72. Dorr W, Noack R, Spekl K, Farrell CL. Modification of oral mucositis by keratinocyte growth factor: single radiation exposure. Int J Radiat Biol. 2001; 77: 341-347.
73. Dorr W, Reichel S, Spekl K. Effects of keratinocyte growth factor (Palifermin) administration protocols on oral mucositis (mouse) induced by fractionated irradiation. Radiotherapy and Oncology. 2005; 75: 99-105.
74. Lucchese A, Matarese G, Ghislanzoni LH,j Giorgio G, Manuelli M, Gherlone E. Efficacy and effects of palifermin for the treatment of oral mucositis in patients affected by acute lymphoblastic leukemia. Leukemia & Lymphoma. 2016; 57(4): 820-827.
75. Vadhan- Raj S, Trent J, Patel S et al. Single- dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer. Ann Intern Med. 2010; 153: 358-367.
76. Brizel DM, Murphy BA, Rosenthal DI et al. Phase II study of palifermin and concurrent chemoradiation in head and neck squamous cell carcinoma. J Clin Oncol. 2008; 26: 2489-96.
77. Luthi F, Berwert L, Frossard V et al. Prevention of oral mucositis with palifermin in patients treated with high- dose chemotherapy and autologous stem cell transplantation. A single center experience. Blood. 2006; 108(11): 2974.
78. Henke M, Alfonsi M, Foa P et al. Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy of head and neck cancer: a randomized, placebo- controlled trial. J Clin Oncol. 2011;29: 2815-20.
79. Le QT, Kim HE, Schneider CJ et al. Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo controlled study. J Clin Oncol. 2011; 29: 2808-14.
80. Shea TC, Kewalramani T, Mun Y, Jayne G, Dreiling LK. Evaluation of single- dose palifermin to reduce oral mucositis(OM) in fractionated total body irradiation (fTBI) and high dose (HD) chemotherapy with autologous peripheral blood progenitor cell (PBPC) transplantation. Blood. 2006; 108(11): 3073.
81. Bartoszewicz N, Czyzewski K, Debski R et al. Efficacy of keratinocyte growth factor in prevention of oral mucositis in children undergoing allogeneic hematopoietic cell transplantation. Acta Haematologica Polonica. 2020; 51(3): 172-178.
82. Spielberger R, Stiff P, Bensinger W et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004; 351: 2590-2598.
83. Stiff PJ, Emmanouilides C, Bensinger WI et al. Palifermin reduces patient- reported mouth and throat soreness and improves patient functioning in the hematopoietic stem- cell transplantation setting. J Clin Oncol. 2006; 24: 5186-5193.
84. Peterson DE. Research advances in oral mucositis. Curr Opin Oncol. 1999; 11: 261-266.
85. Langner S, Staber PB. Palifermin reduces incidence and severity of oral mucositis in allogeneic stem- cell transplant recipients. Bone Marrow Transplant. 2008; 42: 275-279.
86. 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: 1644-1649.
87. Czyzewski K, Debski R, Krenska A, Wysocki M, Styczynski J. Palifermin in children undergoing autologous stem cell transplantation: a matched- pair analysis. Anticancer Research. 2014; 34: 7379-7382.
88. Farrell CL, Bready JV, Rex KL et al. Keratinocyte growth factor protects mice from chemotherapy and radiation induced gastrointestinal injury and mortality. Cancer Res. 1998; 58: 933-939.
89. Kobbe G, Bruns I, Schroeder T et al. A 3-day short course of palifermin before HDT reduces toxicity and need for supportive care after autologous blood stem- cell transplantation in patients with multiple myeloma. Ann Oncol. 2010; 21: 1898-1904.
90. Werner S, Smola H, Liao X et al. The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. Science. 1994; 266: 819-822.
91. Lauritano D, Petruzzi M, Stasio DD, Lucchese A. Clinical effectiveness of palifermin in prevention and treatment of oral mucositis in children with acute lymphoblastic leukemia: a case- control study. International Journal of Oral Science. 2013; 6: 27-30.
92. 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. Critical Reviews in Oncology/ Hematology. 2022; 172: 103606.
93. Blijlevens N, Chateau M, Krivan G et al. In a high- dose melphalan setting, palifermin compared with placebo had no effect on oral mucositis or related patient’s burden. Bone Marrow Transplantation. 2013; 48: 966-971.
94. Stiff PJ, Leinonen M, Kullenberg T, Rudebeck M, Chateau M, Spielberger R. Long- term safety outcomes in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation treated with palifermin to prevent oral mucositis. Biology of Blood and Marrow Transplantation. 2016; 22: 164-169.
95. Brake R, Starnes C, Lu J et al. Effects of palifermin on antitumor activity of chemotherapeutic and biological agents in human head and neck and colorectal carcinoma xenograft models. Mol Cancer Res. 2008; 6: 1337-46.
96. Schmidt V, Niederwieser D, Schenk T et al. Efficacy and safety of keratinocyte growth factor (palifermin) for prevention of oral mucositis in TBI- based allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplantation. 2018; 53: 1188-1192.
97. Logan RM, Al- Azri AR, Bossi P et al. Systematic review of growth factors and cytokines for the management of oral mucositis in cancer patients and clinical practice guidelines. Supportive Care in Cancer. 2020; 28: 2485-2498.