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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 31  |  Issue : 2  |  Page : 162-166

Growth factors in the treatment of oral mucositis in patients receiving treatment for head and neck cancers - A review


1 Department of Oral Medicine and Radiology, Government Dental College and Hospital, Afzal Gunj, Hyderabad, Telangana, India
2 Department of Oral Medicine and Radiology, Panineeya Mahavidhyalaya Institute of Dental Sciences and Research Centre, Dilsukhnagar, Hyderabad, Telangana, India
3 MDS in Oral Medicine and Radiology, Dental Doctor Hyderabad, Hyderabad, Telangana, India

Date of Submission18-Oct-2018
Date of Acceptance04-Aug-2019
Date of Web Publication24-Jun-2019

Correspondence Address:
Dr. Pratima Soni
Department of Oral Medicine and Radiology, Government Dental College and Hospital, Afzal Gunj, Hyderabad - 12, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.jiaomr_176_18

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   Abstract 


Many cancer patients undergoing systemic chemotherapy or radiotherapy or a combination of both, especially in head and neck region, are inherently prone to develop a frequent complication i.e. oral mucositis. This acute and distressing sequel of cancer therapy drastically impairs routine activities such as mastication, deglutition, and speech thereby affecting the overall quality of life of these patients. Because of the complex nature of oral mucositis, its management becomes challenging. An in-depth understanding of the etiopathogenesis of oral mucositis has provided numerous treatment options, but none with a proper guideline. Recent years have also seen a considerable emphasis on growth factors, which has led to the recognition that they might have potential in the therapeutic management of these complications, either by regeneration through biomimetic or mimicking the processes that occur during embryonic and post-natal development. As the understanding of the biological and physiological role of growth factors increases, it is certain that they will play an increasingly important role in clinical insights. This review attempts to highlight the role of growth factors in the management of oral mucositis.

Keywords: Colony-stimulating factor, epidermal growth factor, keratiocyte growth factor, oral mucositis, palifermin, transforming growth factor


How to cite this article:
Soni P, Garlapati K, Kammari A, Guduru H. Growth factors in the treatment of oral mucositis in patients receiving treatment for head and neck cancers - A review. J Indian Acad Oral Med Radiol 2019;31:162-6

How to cite this URL:
Soni P, Garlapati K, Kammari A, Guduru H. Growth factors in the treatment of oral mucositis in patients receiving treatment for head and neck cancers - A review. J Indian Acad Oral Med Radiol [serial online] 2019 [cited 2019 Nov 13];31:162-6. Available from: http://www.jiaomr.in/text.asp?2019/31/2/162/261081




   Introduction Top


Oral mucositis along with xerostomia is one of the most common and a serious complication of anti-neoplastic therapy and occurs with a prevalence of approximately 40% in standard anti-cancer therapies.[1] The term “mucositis” was introduced in late 1980 to describe inflammation of the oral mucosa induced by radiotherapy (RT), chemotherapy (CT), and bone marrow transplantation and is said to be a manifestation of leukopenia.[2],[3] It generally presents shortly after the initiation of treatment and resolves usually within a week. The diagnosis of oral mucositis is according to clinical parameters and is manifested as pain, erythema, and ulcerations on the mucosa, sometimes associated with bleeding.[4]

Oral mucositis that is induced owing to radiation therapy initially manifests as mucosal whitening even before the appearance of erythema and ulceration, and the lesions which are not in the field of RT may be due to candidiasis or reactivation of herpes simplex virus. In contrast, CT oral mucositis presents bilaterally. As CT induces myelosuppression, there is an increased risk of systemic infection. The healing of oral tissues due to mucositis following RT takes 3 to 5 weeks, whereas, in CT-induced oral mucositis, the healing typically occurs in 2 to 3 weeks. Thus, the severity of oral mucositis depends on the dose, time of administration, and sometimes termination of the therapy planned.[5]

Although several clinical scoring systems exist for oral mucositis, but the one most widely used is the grading scale proposed by the World Health Organization as it is easy and suitable for use in routine practice.[6],[7]

  • Grade 0: No oral mucositis
  • Grade 1: Erythema and soreness
  • Grade 2: Ulcers, able to eat solids
  • Grade 3: Ulcers, requires liquid diet (due to mucositis)
  • Grade 4: Ulcers, alimentation not possible (due to mucositis).


[TAG:2]Preventive and Therapeutic Approaches for Oral Mucositis[8],[9],[10][/TAG:2]

A variety of agents have been used for the prevention and management of oral mucositis either in topical form or systemically and are mentioned below[8],[9],[10]

  1. TOPICAL PHARMACOLOGICAL AGENTS


    1. Antimicrobial agents
    2. Antiseptic agents
    3. Anti-inflammatory agents
    4. Mucosal protectants
    5. Local anesthetic agents
    6. Episil (Combination of phospholipids and glycerol dioleate)
    7. Gelclair (Hyaluronic acid)
    8. Matrix metalloproteases blockers


  2. SYSTEMIC PHARMACOLOGICAL AGENTS


    1. Antioxidants
    2. Antifungal agent
    3. Growth factors
    4. Stem cell therapy


  3. ALTERNATIVE AGENTS


    1. Honey
    2. Capsaicin
    3. Chamomile
    4. Coffee
    5. Propolis
    6. Ozonated water


  4. MISCELLANEOUS


    1. Oral care protocol
    2. Cryotherapy
    3. Radiation shields
    4. Low-level laser therapy





   Growth Factors Top


”Growth factors are proteins that stimulate cellular growth, proliferation, and differentiation.” Growth factors and cytokines bind to specific receptors on the cell membrane of target cells.[11] Growth factors are important as they have the capability of affecting a variety of cellular processes, which are important for the regeneration of tissues. Additionally, the self-healing capacity of the patients can be augmented by the use of growth factors.[12]

Growth factors and anti-inflammatory cytokines may be useful in preventing CT and/or RT-induced mucositis. by binding to the receptors of the target cells they help in proliferation of the epithelial cells or help in the recovery of the white blood cells, thereby maintaining the oral health post CT (with or without RT). They also alter the complex balance of pro and anti-inflammatory cytokines involved in the pathogenesis of oral mucositis. A number of such agents have been hypothesized to ameliorate the course of mucositis and are described further.[11],[13]


   Growth Factors in Oral Mucositis Treatment Top


Growth Factors

This group of drugs is the latest addition to mucositis-related research and seems to be the area receiving the most intense amount of interest currently. The efficacy of growth factors greatly varies upon the time of administration, dosage, concentration, duration of contact, or the secretion of drug in the oral environment.[5]

Currently, growth factors are recommended in the prevention of oral mucositis in hematological cancers undergoing high-dose CT and total body irradiation prior to hematopoietic stem cell transplantation.[11]

Recombinant forms of epidermal growth factor (EGF), granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), and, most significantly, keratinocyte growth factor (KGF) seem to be at the center of current studies and have provided inconsistent results.

Keratinocyte growth factor

Recent years have seen a breakthrough in the management of mucositis with the discovery of keratinocyte growth factor; this naturally occurring 28 KDA heparin binding member of the fibroblast growth factor family is capable of binding to its receptor on a variety of epithelial tissues inclusive of oral and gastrointestinal epithelial cells, keratinocytes on skin, stratified squamous epithelial cells hepatocytes, and type 2 pneumocytes.[14] It also has the capability of stimulating the synthesis of DNA in various tissues and exerting its maximal effect on the mucosa of oral cavity and the upper digestive tract.

Endogenous KGF is a potent epithelial mitogen, which is upregulated by the action of platelet-derived growth factor BB and TNF-α.[15]

Palifermin

Palifermin is the first agent approved by FDA for its use in prevention and treatment of oral mucositis in hematological malignancies. It is known to have several biological actions, which target multiple stages in the progression of oral mucositis. Its action is similar to that of endogenous KGF and specifically binds to the tyrosine kinase receptor, uniquely expressed in the oral, gastrointestinal, and skin epithelium.[15]

Palifermin causes proliferation, differentiation, and migration of epithelial cells of tongue and buccal mucosa and increases the epithelial thickening of the squamous epithelium of the oral cavity[16] [Flowchart 1].



Payandeh M,et al. carried out a meta-analysis of 10 studies from 2007 to 2015 on the efficacy of palifermin in oral mucositis and acute Graft Versus Host Disease (GVHD) after hematopoietic stem cell transplant in hematological malignancies and concluded palifermin to be associated with a reduction in the incidence and severity of oral mucositis, whereas no effect was seen in a GVHD.[17]

Le Q, et al. compared palifermin (180 μg/mg) with placebo in a total of 188 head and neck cancer (HNC) patients (94 patients in each group) receiving conventionally fractioned RT (2.0 Gy/day for 5 days per week to 70 Gy) along with cisplatin (100 mg/m2 on days 1, 22, and 93). Their study concluded that palifermin reduced the incidence of severe oral mucositis in patients receiving chemoradiotherapy for Head and neck cancer HNC. Further, it also delayed the development and shortened the duration of oral mucositis providing less use of an opioid analgesic.[18] Similar results were observed in another study conducted by Henke M, et al. in which palifermin was administered at a dose of 120 μg/kg once weekly in HNC patients undergoing postoperative chemoradiotherapy. They observed decrease severity of oral mucositis.[19]

According to the reviewed literature, the administration of palifermin at doses between 1 and180 μg/kg/day reduces the incidence and severity of oral mucositis. The most frequent adverse reactions affect particularly the skin and oral mucosa, with dysgeusia, paresthesia, hypertrophy of the oral mucosa and tongue papillae; color changes of the oral mucosa, rash, pruritus, erythema, and hyperpigmentation of the skin, among other alterations. Other undesirable effects include cough, rhinitis, and arthralgia. These problems are usually mild or moderate in intensity, appear in the last 3 days of treatment, and according to some studies do not require interruption of the drug.[20]

Epidermal growth factor

EGF is an important polypeptide as it helps in epithelial cell proliferation, growth, and migration, thereby maintaining the tissue homeostasis.[13] It is considered as a marker of mucosal damage following a preliminary study, which was conducted in a head and neck cancer patients, wherein elevated levels of EGF were found in the saliva of individuals with oral mucositis.[21]

It is also a molecule that plays a role in wound healing, and its excretion in saliva was found to be reduced after RT. However, literature has shown conflicting results in terms of the relationship of higher levels of salivary EGF with more or less severe mucositis.[4]

Girdler NM conducted A phase I clinical trial on EGF mouthwash and concluded that it does not accelerate ulcer healing, but it may have the potential to protect the oral epithelium from cytotoxic damages.[22] Hong J,et al. in 2009 conducted a study in patients who were undergoing definitive RT of the head and neck region with or without combined CT developed oral mucositis these patients were administered topical rEGF for 7 days twice daily. Their results concluded the effectiveness and safety of rEGF in radiation-induced oral mucositis.[23]

In contrast, a phase 2 clinical trial was conducted by Kim J,et al. in the year 2017 on the efficacy and safety of topical recombinant human epidermal growth factor (rhEGF) in oral mucositis induced by CT with hematopoietic stem cell transplantation. They used rhEGF in the form of oral spray and did not find any evidence for its role in reducing the incidence of oral mucositis.[24]

Literature shows the therapeutic effect of rhEGF in the management of oral mucositis in HNC patients. However, further randomized, controlled clinical trials in large sample size are recommended to optimize the dose, fractionation schedule, and an appropriate method of application.[25]

Transforming growth factor-β

A human recombinant form of TGF- β3 was shown to inhibit reversibly, the cycling of the epithelium, including human buccal mucosa. This polypeptide exerts an anti-proliferative effect on the epithelial and endothelial cells. It also reduces mucositis by arresting the mitosis of epithelial cells in the G1 phase and initiating the regeneration of clonogenic stem cells. It showed a reduction in the severity of oral mucositis when applied topically in patients who received 5-fluorouracil. However, other studies found that the application of TGF-β3 may actually worsen the clinical course of mucositis. These conflicting reports have led to its withdrawal from further clinical development for oral mucositis.[26],[27]

Colony-stimulating factors

Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) were the first group of growth factors to have been tried in oral mucositis. These are the hematopoietic growth factors needed for the bone marrow progenitor cells to form mature blood cells. The CSFs are the G-CSF and GM-CSF. G-CSF stimulates the development of neutrophils, eosinophils, and basophils, whereas the GM-CSF stimulates the generation of cells belonging to the monocyte/macrophage lineage. Both the factors enhance the functioning of peripheral neutrophils including those in mucosal tissues. The rationale behind numerous clinical trials on G-CSF and GM-CSF can be attributed to its direct action on the peripheral neutrophils, thereby reducing neutropenia induced during CT, hence decreasing the infection and oral mucositis.[28]

Patni N,et al. evaluated the response of GM-CSF (100 mcg per day subcutaneously) in radiation-induced mucositis in a total of 33 patients with stage I and II head and neck squamous cell carcinoma. Treatment with GM-CSF was initiated only when patchy fibrinous mucositis was observed, pain not responding to step 1 pain killers (WHO step ladder), and when difficulty in swallowing semisolid food was present. They concluded a decrease in the severity of oral mucositis, dysphagia, and reduced pain not requiring the use of opioid analgesics. Minimal side effects were observed and 2 patients out of 33 reported itching and erythema at the site of injection.[29]

Other clinical trials investigating the topical use of GM-CSF in the form of mouthwash has yielded no evidence to support its use.[30],[31]


   Conclusion Top


Oral mucositis is the most significant dose – limiting step in the cancer treatments and is associated with adverse effects. Reducing the morbidity of mucositis will help to avoid unwanted dose reductions or unscheduled breaks in cancer therapy and thus improve outcomes of cancer therapy. Till date, there is no effective gold standard treatment for oral mucositis. Literature has several good experimental evidences to support the use of growth factors in treating oral mucositis. However, there are numerous families of growth factors, which have already been identified with some of them in preclinical trials, and few have already been tried in animals and humans with good clinical efficacy. Currently, Palifermin (KepivanceTM) is the only FDA approved agent for the treatment of oral mucositis in hematological malignancies. It targets several stages of oral mucositis by multiple biological activities. The role of palifermin in the management of oral mucositis in head and neck cancer patients undergoing chemoradiotherapy should be further established for its safety and dosing schedule. However, in spite of extensive research on various families of growth factors, there is still existing lacuna in the effective prevention and treatment of oral mucositis, which embarks the need for development of accurate, easy to use, and cost-effective intervention.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Raber-Durlacher JE, von Bültzingslöwen I, Logan RM, Bowen J, Al-Azri AR, Everaus H, et al. Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients. Support Care Cancer 2013;21:343-55.  Back to cited text no. 13
    
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Danilenko D. Preclinical and early clinical development of keratinocyte growth factor, an epithelial-specific tissue growth factor. ToxicolPathol1999;27:64-71.  Back to cited text no. 14
    
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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.  Back to cited text no. 15
    
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Pinakini K, Bairy K. Palifermin: A keratinocyte growth factor for oral mucositis. Indian JPharmacol 2005;37:338.  Back to cited text no. 16
    
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Payandeh M, Sadeghi M, Ramezani M, Reza Mozaffari H. The efficacy of paliferminon oral mucositisand acute GVHD after hematopoietic stem cell transplantation in hematologic malignancy patients: A systematic review and meta-analysis study. Biomed Res Ther 2017;4:1676.  Back to cited text no. 17
    
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Le Q, Kim H, Schneider C, Muraközy G, Skladowski K, Reinisch S, et al. Paliferminreduces severe oral mucositisin subjects with locally advanced head and neck cancer undergoing chemoradiotherapy. Int J RadiatOncolBiolPhys2008:72:S32-3.  Back to cited text no. 18
    
19.
Henke M, Alfonsi M, Foa P, Giralt J, Bardet E, Cerezo L, et al. Palifermindecreases severe oral mucositisof patients undergoing postoperative radiochemotherapyfor head and neck cancer: A randomized, placebo-controlled trial.J ClinOncol2011;29:2815-20.  Back to cited text no. 19
    
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24.
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