Management of Chemotherapy and Radiation-Induced Oral Mucositis in Cancer Patients

O’Neill S, Mirza HN and Younus J

Published on: 2020-08-30

Abstract

Oral mucositis (OM) is a common side effect induced by cancer therapy. Despite its prevalence, there is currently no standardized management protocol for treating and/or preventing OM. This paper reviews prevention and treatment strategies for oral mucositis in cancer patients and presents an algorithm to aid health care professionals.

Keywords

Mucositis; cancer; radiation; chemotherapy; oral cavity

Introduction

Oral mucositis (OM) is one of the most common and irritable side effects induced by chemotherapy and/or radiation treatment. These painful oral lesions occur in 20-40% of patients receiving chemotherapy, and 76% of patients receiving high-dose chemotherapy before hematopoietic stem-cell transplantation (HSCT) [1,2]. Over 90% of patients treated for mouth and oropharynx cancer also develop severe OM [3]. Opioid-level analgesics are often required to manage mucositis-related pain [4]. The severe discomfort that accompanies OM not only affects the patient’s quality of life and ability to eat, but can delay treatment protocols and negatively impact a patient’s prognosis as well. Currently, there is no agreed upon management protocol for treating and preventing oral mucositis in such patients. The aim of this paper is to summarize study results for preventing or treating mucositis in cancer patients at risk of developing OM and aid health care professionals by providing a management algorithm.

Risk factors

Risk factors associated with OM are divided into two categories. Patient-related risk factors describe factors inherent to the patient themselves, while cytotoxic risk factors describe factors inherent to the patient’s treatment protocol. Patient-related OM risk factors have not been well established, however cytotoxic risk factors are supported by clinical experience (see Tables 1 and 2).

Table 1: Patient-related risk factors for oral mucositis development [11,12,14-21].

Risk Factor	Effect on Risk	Pathophysiology
Age	Increase Mixed findings	Very young- higher epithelial mitotic rate Elderly- decreased rate of healing, decreased renal filtration (increased risk) versus slower epithelial mitotic rate (decreased risk)
Gender Genetics	Mixed findings Decrease	Potentially increased risk in females Some individuals may have OM resistance
Salivary secretion function	Increase	Decreased saliva production
Body mass index (BMI)	Increase	Poor nourishment- increased breakdown, delayed healing
Renal function	Increase	Elevated creatinine
Smoking	Increase	Poor microcirculation may delay healing
Previous cancer treatment Oral disease (prior to treatment)	Increase Increase	History of OM during previous cancer treatment Chemotherapy-induced OM

Table 2: Cytotoxic risk factors for oral mucositis development [17,22-25].

Risk Factor	Contribution to OM
Radiation site and fractionation	Higher doses in head and neck region carries greater risk
Chemotherapy drug/dose	Antimetabolites, antitumor antibiotics, alkylating agents, etc. Specifically:
	Cytarabine
	Doxorubicin
	Etoposide (high-dose)
	Melphalan (high-dose)
	Fluorouracil (FU)
Type of transplant Combined therapy	Allogenic transplant carries greater OM risk than autologous Combined chemotherapy and radiation increases OM risk

In addition to cytotoxic drugs most commonly linked to OM (Table 2), Mucositis is also reported in 30-40% of patients treated with receptor tyrosine kinase inhibitors (e.g., sunitinib, sorafenib, lenvatinib, and regorafenib), 25% of patients treated with cyclin-dependent kinase 4/6 inhibitor (e.g., palbociclib), and in 10-20% of patients treated with epidermal growth factor receptor targets (e.g., cetuximab and erlotinib) [5,6]. Oral mucositis has also been documented in patients treated with afatinib (blocks signals from the epidermal growth factor receptor), and in up to 70% of patients treated with rapamycin (mTOR) inhibitors (e.g., temsirolimus and everolimus) [6-10]. In general, treatment with molecularly targeted agents may lead to less severe mucositis than cytotoxic agents [6]. Genetic factors (e.g. polymorphisms in drug metabolizing enzymes, pro-inflammatory cytokines) may provide potential resistance to OM in some individuals, though there is insufficient evidence [11,12]. Other risk factors that may affect OM severity include nutrition, type of malignancy, oral care during treatment, pretreatment neutrophil counts and hematopoietic growth factor support during treatment [13,14].

Clinical Description

Patients with oral mucositis often present with any combination of the following symptoms: changes in sensation, difficulty talking and swallowing, presence of mouth sores, and dryness [15-25]. Mucositis may also increase a patient’s risk of infection, which can lead to treatment interruptions or dose reductions [26].

Oral mucositis usually appears within 7-14 days after the initiation of chemotherapy or radiation [27]. Radiation-induced OM typically appears at doses of 10-20 Gy of standard fractionated head and neck radiation, and is worsened by cumulative doses [27]. Unlike radiation-induced OM, where damage is usually limited to the field of radiation, chemotherapy-induced OM may affect the non-keratinized mucosa of the soft palate, ventral tongue/floor of mouth, and buccal and labial mucosa [27]. Mucosal lesions spontaneously begin to resolve within several days and are typically healed within 10-14 days after chemotherapy administration, or 3-6 weeks following radiotherapy [27]. A review of the stages of OM is presented in Table 3.

Table 3: Stages of oral mucositis [3,28].

Stage	Description
Stage 1: Initiation	Radiation and chemotherapy damage both DNA and non-DNA targets, and reactive oxygen species are produced
Stage 2: Upregulation and message generation	Transcription factor nuclear factor-kappa B is activated, leading to the production of a variety of biologically active proteins
Stage 3: Signaling and amplification	Accumulated pro-inflammatory cytokines damage surrounding tissue, and feedback to amplify primary damage
Stage 4: Ulceration and inflammation	Loss of mucosal integrity results in painful lesions susceptible to bacterial colonization
Stage 5: Healing	In most cases, mucositis is acute and self-resolving once cancer therapy has ceased

The most commonly used grading system for oral mucositis is the National Cancer Institute Common Technology Criteria. The most recent version (v5.0) assesses oral mucositis severity on a scale from 1 to 5 based on symptoms and clinical findings (see Table 4) [29].

Table 4: NCI CTCAE v5.0 mucositis oral.

Adverse Event	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Oral mucositis	Asymptomatic or mild symptoms; intervention not indicated	Moderate pain, not interfering with oral intake; modified diet indicated	Severe pain, interfering with oral intake	Life-threatening consequences; urgent intervention indicated	Death

Definition: A disorder characterized by ulceration or inflammation of the oral mucosa NCI CTCAE: National Cancer Institute Common Technology Criteria for Adverse Events Reproduced from: Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, November 2017, National Institutes of Health, National Cancer Institute.

Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf

Treatment Options and Algorithm

Patients receiving cancer therapy should be educated on the risks and incidence of oral mucositis in the event that they should develop OM. This section outlines the effectiveness of available prevention and treatment strategies (Tables 5, 6) and provides algorithms for health care professionals managing patients with OM in a general setting and for select cancer types/treatments (Figures 1,2).

Figure 1: Proposed algorithm for prevention of oral mucositis in cancer patients.

Ideally, patients should be treated for oral mucositis until severity decreases to grade 1 or symptoms resolve completely. Duration of treatment depends on the treatment strategy used and varies between patients based on individual factors, type of cancer and treatment protocol.

Based on this literature review, benzydamine, cryotherapy, dexamethasone, low level laser therapy, oral care protocol and palifermin are supported strategies for preventing OM in patients receiving cancer therapy (Table 5). Specifically, evidence supports cryotherapy, low level laser therapy (LLLT) and palifermin for patients receiving hematopoietic stem cell transplant (HSCT), dexamethasone for hormone receptor positive metastatic breast cancer patients treated with mTor inhhibitors and benzydamine for patients receiving radiation therapy. It may be beneficial for physicians to recommend cryotherapy and oral care protocols to all patients who are at risk of developing OM due to their less invasive nature. We suggest that these six treatment modalities be studied against each other and a control in the future to provide a ranked algorithm for OM prevention.

Benzydamine (0.15%) oral rinse reduces erythema and ulceration in patients receiving radiation (≤ 50 Gy) and can delay use of systemic analgesics compared to placebo [30]. Newer studies suggest that benzydamine may also be effective for preventing OM at doses ³ 60 Gy in head and neck cancer patients [31].

Cryotherapy reduces the incidence of any severity OM in 5-FU patients, and can prevent severe OM in patients receiving high-dose melphalan before HSCT [32]. Cryotherapy can be prescribed by recommending that patients keep their mouth cold with ice, ice-cold water, popsicles, etc. Low rates of minor adverse effects (i.e. headaches, chills, numbness, tooth pain) are reported with cryotherapy, therefore high compliance rates can be expected.

Dexamethasone mouthwash (0.5 mg/5 mL) reduces the incidence and severity of grade ³ 2 stomatitis in metastatic breast cancer patients treated with everolimus and exemestane [33]. Patients treated with dexamethasone reported a mean pain scale score < 1 and 86% reported a normal diet at 8 weeks [33].

Low level laser therapy (LLLT; 632.8-660 nm) significantly decreases the incidence and duration of severe (grade 3-4) OM [34-36]. A six-fold decrease in grade 3/4 OM incidence (6.4%) was reported compared to placebo (40.5%) [34]. In addition, more patients treated with LLLT were ulcer-free (59.6%) versus placebo (21.3%) [34]. Duration of severe OM was significantly less when patients were treated with LLLT (8.19 ± 5.14 days) versus placebo (12.86 ± 6.61 days) [36]. Low level laser therapy was also associated with decreased oral pain, opioid analgesic use and dysphagia [36]. No LLLT related toxicity was reported [34-36].

Palifermin (180 µg/kg) decreases the incidence of grade 3/4 OM (51% versus 67%) compared to placebo [37]. Palifermin was also associated with decreased duration (4.5 versus 22 days) and delayed progression to severe (grade 3/4) OM (45 versus 32 days) versus placebo [37].

Despite weaker supporting evidence than the recommended strategies above, information on basic oral care (including brushing, flossing and mouth rinses) should be provided to all patients at risk of developing OM. With proper regime and technique education, patients may reduce their risk of OM incidence and severity. In one study, significantly fewer patients on oral care protocol (30%) developed stage 3 OM by week 7 versus control (76.7%) [38]. Reports of severe and very severe pain by week 7 were also less in the treatment group (5%) versus control (56.7%). The 2014 Cochrane review suggests oral care protocols for OM prevention, but states that current evidence is not strong enough to support a recommendation [39].

This review does not extend the OM treatment algorithm to rank pain management strategies. Appropriate pain management with local or systemic administration is recommended based on symptom severity and individual patient presentation.

Literature on complementary medicine strategies for treating and preventing OM were also reviewed, as we acknowledge the increasing interest in this field by patients and physicians. Although there could be many potential candidates from the complementary medicine side, none of the agents or combination had any strong evidence to be included as a recommendation for the prevention or treatment of OM. The Following three complementary medicine options may have more potential than others and are therefore mentioned here in summary. ATL104- is a recombinant protein that may work through stimulation of cells that line the digestive tract. This compound has gone through few human clinical trials with promising results and other trials are being conducted [40].

SAMITALÒ (Vaccinium myrtillus, Macleaya cordata fruits and Echinacea angustifolia roots extract) was used as a treatment in head and neck cancer patients receiving radiation and chemotherapy. It was shown to reduce OM severity and pain [41]. Zinc supplements is an over the counter product that may prevent OM in patients receiving radiation and chemotherapy [42]. In further prevention strategies, Lin et al. (2010) found that zinc may delay grade 2-3 OM in oral cancer patients [43].

Table 5: Strategies for preventing oral mucositis (OM).

Therapy	Cancer Treatment	Efficacy Parameter	Notes	Reference
Benzydamine 0.15% oral rinse	R	Reduced OM incidence severity and analgesic use in H&N patients receiving R (≤ 50 Gy) without concomitant C	Strongest guideline for ≤ 50 Gy	[30]
Benzydamine 0.15% oral rinse	R	Reduced incidence, severity ³ 60 Gy in H&N patients		[31]
Cryotherapy (30 mins)	C	Reduced incidence of OM (any severity) in fluorouracil patients Reduced incidence of severe OM in patients receiving melphalan before HSCT		[32]
Dexamethasone mouthwash (0.5 mg/5 mL)	C	Reduced incidence and severity of grade ³ 2 stomatitis in women with HR+ metastatic breast cancer treated with everolimus and exemestane		[33]
Low level laser therapy (LLLT) (632.8-660 nm)	R+C	Reduced incidence of grade 3-4 OM, severity, decreased pain, analgesic use, dysphagia in H&N cancer. Strongest evidence for HSCT patients	Interaction of LLLT with R not yet clarified	[34-36]
Oral care protocol	R+C	Suggested for OM prevention across all treatment modalities	Brushing, flossing, oral exams, mouth rinses	[38,39]
Oral care protocol	R	Reduced incidence, pain, delayed progression	(i.e. sodium bicarbonate, saline water)	[38,39]
Palifermin (keratinocyte growth factor-1)	R+C	Reduced incidence and duration and delayed onset of severe OM in autologous HSCT patients		[37,44]

Figure 2: Proposed algorithm for treatment of oral mucositis in cancer patients.

Table 6: No guideline possible for preventing/treating oral mucositis (OM) due to conflicting or insufficient evidence.

Therapy	Indication	Cancer Treatment	Preliminary Results	Reference
Acyclovir	P	R+C	No reduction in OM incidence May reduce OM incidence for seropositive herpes simplex virus patients with acute myeloid leukemia	[45,46]
Allopurinol mouthwash	P	C	May reduce oral toxicity of FU-induced OM	[47]
	P	C	No protective effect against FU-induced OM	[48]
	T	C	May treat methotrexate-induced OM in rheumatoid arthritis patients	[49]
Betamethasone	T	C	Reduced OM severity but honey, and honey + coffee treatment had greater effect	[50]
Chlorhexidine	P	BMT	Reduced incidence and severity of OM in HSCT patients and GI patients receiving FU with leucovorin	[51,52]
	P	C		[51,52]
	P	C	No reduction in OM incidence or severity compared with sterile water mouthwashes	[53]
	P	R	Not recommended for H&N patients	[54]
Colchicine mouthwash	T	C	Reduced duration and severity of OM in hematology patients No reduction in pain	[55]
Colony stimulating factors (GM-CSF and G-CSF)	P	C	G-CSF- reduced incidence and severity of grade ³ 2 OM in urothelial carcinoma patients	[56]
	P	R+C	G-CSF- Filgrastim (r-metHuG-CSF) may decrease severity and incidence in lung cancer and H&N patients	[57,58]
	P	C	GM-CSF- reduced incidence, duration of grade ³ 3 OM in H&N patients	[59]
	P+T	R+C	GM-CSF- no reduction in OM incidence, severity, pain, duration in H&N patients	[60,61]
	P	HSCT	Not recommended for patients receiving high-dose C	[39]
Doictahedral Smecite and Iodine Glycerine Cream (DSIG)	T	C	Reduced OM severity and duration compared to topical mouth rinse (saline, gentamicin and vitamin B₁₂)	[62]
Erythropoietin mouthwash (50 IU/mL)	P	C	Reduced incidence, severity, duration of OM in HSCT patients	[63]
Fluconazole	P	R	Reduced severity of candidiasis and/or presence of Candida albicans	[64,65]
Glutamine	P	R	Oral supplements may reduce duration and severity. May shorten duration of Grade ³ 3 OM in H&N patients	[66]
	P	C	Oral supplements do not prevent FU-related OM in GI patients	[67]
	P+T	C	Saforis (oral L-glutamine) reduced incidence of grade ³ 2 in breast cancer patients treated with anthracycline and cyclophosphamide	[68]
	P	R+C	Intravenous l-alanyl-l-glutamine may reduce incidence, severity, pain in H&N patients	[69]
	P	HSCT	Intravenous glutamine not recommended for HSCT patients receiving high-dose C ± R	[39]
Intestinal trefoil factor oral spray	P+T	C	Reduced incidence of grade ³ 2 OM in colorectal cancer patients receiving FU-based C	[70]
Irsogladine maleate	P	C	Reduced incidence of FU-induced OM	[71]
Lactobacillus brevis CD2 lozenges	P	R+C	Reduced incidence of grade ³ 3, and overall OM in H&N patients Higher rate of treatment completion	[72]
Mixed medication “Magic” mouthwash	T	R+C	Diphenhydramine/lidocaine/antacid (DLA) mixture reduces pain in H&N patients Mouthwash formulations vary	[73]
Mucoadhesive hydrogel “MuGardÒ”	T	R+C	Reduced mouth/throat soreness in H&N patients	[74]
N-acetyl cysteine	P	C	Reduced incidence of severe (grade ³ 3) OM, reduced duration in HSCT patients	[75]
OctenidolÒ	P	C	Reduced oropharyngeal flora in HSCT patients	[76]
Palifermin (keratinocyte growth factor-1)	P	HSCT	No benefit for allogenic HSCT patients	[77]
	P	C	No effect on grade 3-4 OM in acute myeloid leukemia patients receiving idarubicin, high-dose cytarabine and etoposide	[78]
	P	C	Reduced incidence and severity of grade ³ 2 OM in patients receiving multiple cycles of ifosfamide and high-dose doxorubicin	[79]
	P	C	Reduced incidence of grade ³ 2 OM in colorectal cancer patients receiving bolus FU-based C	[80]
Phenylbutyrate 5% mouthwash	T	R+C	Reduced OM severity in H&N patients Most effective 55-75 Gy	[81]
Platelet gel	P	R	Delayed OM onset and reduced toxicity in grade 3/4 OM in H&N patients	[82]
Polaprezinc (lozenge or zinc-L-carnosine suspension in sodium alginate solution)	P	C	Lozenge- reduced incidence of grade 2, lower overall grade of OM, and reduced pain in HSCT patients	[83]
	P	R	Suspension- reduced incidence of grade 3 OM and duration of radiotherapy in H&N patients	[84]
Povidone iodine 1% mouthwash	P	R+C	Reduced incidence, duration, severity in H&N patients	[85,86]
Povidone iodine 1% mouthwash	P+T	HSCT	No effect on HSCT patients	[87]
Propantheline	P	HSCT	Reduced incidence and severity in patients receiving high-dose etoposide before HSCT	[88,89]
Prostaglandins	P	R+C	No reduction in OM incidence or duration in H&N, high-dose ICE, or BMT patients	[90-92]
Repifermin (keratinocyte growth factor-2)	P	HSCT	Reduced incidence of grade 2-3 OM in HSCT patients, reduced pain 50 μg/kg may be optimal dose	[93]
RhEGF (human recombinant epithelial growth factor)	P	R	Reduced incidence of severe OM in H&N patients May delay onset and reduce severity of recurrent ulcers in lung cancer patients	[94]
RhEGF (human recombinant epithelial growth factor)	P+T	C	Potential unfavorable effects on tumor growth	[95]
Triclosan 0.03% mouthwash	T	R	Reduced incidence of grade ³ 4 OM, accelerated symptom resolution	[96]
Triamcinolone acetonide	T	R	Reduced pain and mean OM scores in H&N patients No significant difference between triamcinolone acetonide and licorice mucoadhesive film	[97]

P- prevention; T- treatment; C- chemotherapy; R- radiation; FU- fluorouracil; Gy- Gray; HSCT- hematopoietic stem cell transplant; H&N- head and neck cancer; BMT- bone marrow transplant; GI- gastrointestinal cancer; GM-CSF- granulocyte-macrophage colony-stimulating factor; ICE- ifosfamide, carboplatin, etoposide chemotherapy.

Summary

Oral mucositis associated with chemotherapy and radiation is a very common and irritating side effect faced by cancer patients. OM presents a challenging clinical problem for physicians as it can delay treatment protocols and worsen prognosis in some cases. The algorithm presented here aims to aid in the treatment and prevention of oral mucositis to improve quality of life for cancer patients and allow their treatment protocol to continue as scheduled.

Journal of Cancer Research and Clinical Practice

Management of Chemotherapy and Radiation-Induced Oral Mucositis in Cancer Patients

Abstract

Keywords

Introduction

Summary

References