INTRODUCTION — Oral complications resulting from systemic anticancer therapy include mucositis, saliva changes, taste alterations, infection, and gingival bleeding. [1,2]. All of these complications can cause pain and/or impair nutrition.
Disruptions in the function and/or integrity of the mucosal lining of the gastrointestinal tract are a particularly important problem in patients receiving chemotherapy. Mucositis, which reflects a short-term, self-limited adverse effect of treatment, can affect the entire alimentary tract. The range of symptoms includes oral ulcerations, dysphagia and odynophagia, esophagitis, gastritis, diarrhea, and malabsorption.
Chemotherapy-associated acute oral toxicity will be reviewed here. Oral mucositis in the setting of high-dose chemotherapy and hematopoietic cell transplantation is discussed in detail elsewhere, as are radiation-induced oral mucositis, osteonecrosis of the jaw related to use of antiresorptive therapy and angiogenesis inhibitors in patients with advanced cancer, and late oral toxicities in cancer survivors. (See "Management and prevention of complications during initial treatment of head and neck cancer" and "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Mucositis' and "Oral health in cancer survivors" and "Medication-related osteonecrosis of the jaw in patients with cancer" and "Early complications of hematopoietic cell transplantation", section on 'Oral mucositis'.)
MUCOSITIS — Oral mucositis affects on average 20 to 40 percent of patients receiving conventional-dose cytotoxic chemotherapy [3-5]. The frequency is higher (up to 80 percent) in those undergoing hematopoietic cell transplantation (HCT), particularly myeloablative allogeneic HCT, and in those who are prepared with radiation-containing regimens and with the use of methotrexate for graft-versus-host disease prophylaxis. An exception is in the setting of reduced-intensity or non-myeloablative allogeneic HCT, where mucositis is rare. (See "Early complications of hematopoietic cell transplantation", section on 'Oral mucositis'.)
Pathobiology — The pathobiology underlying damage to the oral mucosal barrier is complex, and a series of stages has been described in patients treated with conventional cytotoxic chemotherapy agents, summarized as follows [3-5]:
●Initiation – Chemotherapy and radiation therapy damage both DNA and non-DNA targets, both as a direct effect and mediated through reactive oxygen species.
●Upregulation and generation of messenger signals – The initial injury activates the transcription factor nuclear factor-kappa B, leading to the production of a variety of biologically active proteins, including proinflammatory cytokines.
●Signaling and amplification – As proinflammatory cytokines accumulate, they damage surrounding tissues directly, and the effect is amplified via feedback loops. This phase precedes the development of overt clinical mucositis.
●Ulceration and inflammation – Loss of mucosal integrity results in clinically painful lesions and allows secondary bacterial colonization.
●Healing – Mucositis generally is self-limited, and healing begins once the tissue insult is withdrawn.
Etiology and risk factors — Multiple factors influence the extent and severity of mucositis, including the specific drug, dose, route and frequency of administration, individual patient tolerance, genetic variants in drug metabolizing pathways, immune signaling and cell injury/repair mechanisms, and possibly smoking history [6]. The most robust data support dosimetric parameters as key predictors of mucositis risk. A comprehensive list of cancer treatment drugs with the potential to cause oral mucositis is provided in the following table (table 1).
Specific anticancer agents
●Cytotoxic chemotherapy agents – In general, chemotherapeutic agents that are DNA cell cycle specific (eg, bleomycin, fluorouracil [FU], and methotrexate) are more stomatotoxic than those that are cell phase nonspecific (eg, cyclophosphamide, cisplatin, anthracyclines) [7]. Certain drugs (eg, methotrexate, etoposide) may be secreted into the saliva [8-10], and it is postulated that this might increase the potential for stomatotoxicity.
The conventional cytotoxic drugs used to treat cancer that are most commonly associated with mucositis are:
•Etoposide (high-dose)
•Melphalan (high-dose)
•FU (bolus administration schedules)
●Molecularly targeted agents – The range of reported rates of stomatitis in patients receiving molecularly targeted agents is broad, and depends on the class of agent:
•Oral mucositis is reported in 30 to 40 percent of patients receiving therapy with the molecularly targeted agents sunitinib, sorafenib, lenvatinib, and regorafenib (which are orally active receptor tyrosine kinase inhibitors that target, among others, vascular endothelial growth factor receptors), in 25 percent of patients treated with the cyclin-dependent kinase 4/6 inhibitor palbociclib, in 20 percent of patients treated with the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib, and in 10 to 46 percent of patients treated with agents that target the epidermal growth factor receptor (EGFR), such as cetuximab, erlotinib, dacomitinib, and mobocertinib; most cases are mild to moderate [11-13].
•Higher rates of stomatitis (72 percent all grade, 9 percent grade 3 or worse) are reported with afatinib, which blocks signaling from the EGFR1, (erbB1), EGFR2 (HER2/erbB2), and erbB4 [14], and with the oral fibroblast growth factor receptor inhibitors erdafitinib (56 percent all grade, 9 percent grade 3 or worse), and infigratinib (56 percent all grade, 15 percent grade 3 or 4) [15,16]. Most cases with all of these agents are mild. (See "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Oral toxicity'.)
•In addition, oral mucosal lesions (both typical ulcerations caused by loss of mucosal integrity and discrete aphthous-like ulcerations with an underlying inflammatory mechanism) have been seen in up to 73 percent of patients treated with the mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitors temsirolimus and everolimus; they are severe (grade 3 or worse, (table 2)) in approximately 4 to 8 percent [12,17-25]. In a review, mTOR inhibitor-associated stomatitis was the most frequent adverse event overall associated with these drugs (73 percent), accounted for almost 30 percent of dose reductions, and was the most frequent dose-limiting toxicity (53 percent) [25].
●Immune checkpoint inhibitors – Mucosal toxicities associated with the use of immune checkpoint inhibitors include periodontal disease and stomatitis, as well as oral lichen planus, xerostomia, and rarely, a Sjögren's-like syndrome affecting the salivary glands, and mucous membrane pemphigoid-like lesions [26,27]. This subject is discussed in detail elsewhere. (See "Mucocutaneous toxicities associated with immune checkpoint inhibitors", section on 'Mucosal toxicities'.)
Preexisting oral disease — Oral disease that is present prior to treatment is thought to increase the risk of chemotherapy-induced mucositis. Within the general population, up to 75 percent have chronic periodontal disease [28-30]. (See "Epidemiology, pathogenesis, and clinical manifestations of odontogenic infections".)
A number of dental conditions have been causally linked with an increased risk for stomatotoxicity, based upon empiric evidence and published data [31,32]. These include:
●Poor oral hygiene
●Caries and associated periapical pathology
●Periodontal disease
Other factors — Younger patients have a relatively greater risk of chemotherapy-induced stomatitis, perhaps related to a higher epithelial mitotic rate [33]. Other factors that may modulate the severity of stomatitis include nutritional status, the specific treatment protocol, the quality of oral care during treatment, pretreatment neutrophil counts, the use of hematopoietic growth factor support during therapy, and differences in the oral microbiome [5,32,34,35].
A role for genetic susceptibility (eg, inherited polymorphisms in drug-metabolizing enzymes and proinflammatory cytokines) is likely but not yet proven [36-38].
Clinical manifestations
●Conventional cytotoxic agents – For conventional cytotoxic agents, direct stomatotoxic effects typically start at day 7 and peak by day 10 to 14.
The initial clinical manifestation is soft tissue erythema of the buccal mucosa or soft palate with a burning sensation in the mouth. This stage may be followed by the development of solitary, elevated, white desquamative patches that are slightly painful. With further progression, epithelial sloughing results in multiple shallow ulcerations with a pseudomembranous appearance (picture 1), which coalesce to form large, painful ulcerations and cause dysphagia and reduced oral intake.
The severity ranges from mild mouth soreness with a paucity of clinical findings to severe erosive mucositis that is accompanied by severe pain and an inability to eat or drink. Severe pseudomembranous or erosive mucositis can lead to secondary infection or sepsis (particularly in the presence of concomitant neutropenia), and necessitate the use of parenteral nutrition and/or opiates. In addition, oral or gingival bleeding can occur if the patient becomes thrombocytopenic. Occasionally, pain may precede the mucosal changes. (See 'Infectious complications' below.)
Mucositis is typically a self-limited phenomenon. Following conventional cytotoxic chemotherapy, which is typically administered episodically in cycles, the mucosal lesions spontaneously begin to resolve within several days and are usually completely healed within 10 to 14 days after onset, frequently improvement is concurrent with neutrophil recovery [30]. Severe (grade 3 or 4) symptoms may necessitate dose reduction during subsequent treatment cycles. However, only rarely is cessation of therapy required because of severe mucosal toxicity (eg, in a patient with dihydropyrimidine dehydrogenase deficiency who is receiving FU). (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Fluorouracil'.)
●Molecularly-targeted agents – In general, the oral mucositis seen with molecularly targeted agents tends to be of a lesser severity than with conventional cytotoxic agents [12,39]. (See 'Specific anticancer agents' above.)
The time to onset is typically earlier (two to three days after treatment initiation) with molecularly targeted agents, especially with mTOR inhibitors. With episodic administration (eg, cetuximab), mucositis is typically self-limited. However, for tyrosine kinase inhibitors that are dosed continuously on a daily basis, mucositis may be continuous, although it may lessen over time or with weeks off of therapy, depending on the specific agent.
The clinical appearance is distinct from that associated with conventional cytotoxic agents. It is almost exclusively aphthous-like and well-defined (picture 2 and picture 3).
●Immune checkpoint inhibitors –The mucositis associated with immune checkpoint inhibitors has a variable presentation, but often with lichenoid features. Oral lichenoid reactions typically present with reticulate, white streaks (Wickham striae) or erosive lesions. While the mucositis is potentially severe, it is generally low-grade. This subject is discussed in detail elsewhere. (See "Mucocutaneous toxicities associated with immune checkpoint inhibitors", section on 'Mucosal toxicities'.)
Grading severity — A variety of grading systems incorporating both subjective and objective criteria have been utilized to define the severity of mucositis. The most commonly used, the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), grades the severity of mucositis on a scale from 1 to 5, based upon the clinical findings and symptomatology; the most recent version is outlined in the table (table 2).
The World Health Organization also has a grading scale, as follows:
●Grade 0 – No oral mucositis
●Grade 1 – Erythema and soreness
●Grade 2 – Ulcers; able to eat solid food
●Grade 3 – Ulcers; but requires liquid diet (due to mucositis)
●Grade 4 – Ulcers; alimentation not possible due to mucositis
Another scale, the University of Nebraska Oral Assessment Score, has been used to evaluate the clinical course of mucositis in recipients of high-dose therapy and HCT [40]. It assigns a numeric grade to eight different aspects of the oral assessment (possible range of scores, 8 to 24). Patients with higher peak mucositis scores (≥18 versus <18) had a significantly greater incidence of positive blood cultures (60 versus 30 percent) and a higher transplant-related mortality rate (24 versus 4 percent). (See "Early complications of hematopoietic cell transplantation", section on 'Oral mucositis'.)
Infectious complications — An intact oral mucous membrane creates a physical barrier to pathogens and provides clearance of adhering microorganisms through the regular sloughing of surface epithelial cells [4]. Breakdown of the mucosal barrier predisposes to bacterial, fungal (especially Candida albicans), and viral superinfection, particularly as the hematologic nadir is reached after chemotherapy. The incidence and severity of infectious complications rise when the absolute neutrophil count (ANC) falls below 1000/microL.
An altered mucosal barrier can serve as the portal of entry for translocation of a variety of pathogens, including viruses, fungi, and bacteria into the bloodstream [3,41,42]. A relationship between mucositis and systemic bacteremia was shown in a study of 69 patients undergoing autologous HCT [42]. Patients who developed alpha hemolytic streptococcal bacteremia (n = 24) were significantly more likely to have ulcerative mucositis (62 versus 36 percent), and in turn, the presence of ulcerative mucositis increased the likelihood of developing bacteremia threefold.
Oral candidiasis — As noted above, the most common superinfecting organism in patients with chemotherapy-induced mucositis is Candida albicans. Many of these patients are already at risk for superficial oral candidiasis because they are immunocompromised as a result of their advanced cancer.
Mucositis also increases the risk that a superficial infection will disseminate [7,43]. As an example, in one series of patients undergoing high-dose chemotherapy for acute leukemia, systemic fungemia occurred almost exclusively in those with prior oropharyngeal candidiasis [43]. (See "Esophageal candidiasis in adults".)
Superficial oropharyngeal candidiasis can be treated topically with clotrimazole troches or nystatin suspension. Systemic therapy with oral fluconazole is generally not needed unless the patient cannot tolerate topical therapy. Refractory infection may require oral or parenteral fluconazole, or parenteral amphotericin B. (See "Oropharyngeal candidiasis in adults".)
HSV reactivation — Given the high risk of reactivation, antiviral prophylaxis is indicated for herpes simplex virus (HSV)-seropositive patients who are undergoing either induction chemotherapy for acute leukemia or receiving high-dose "conditioning" regimens followed by HCT.
In the absence of antiviral prophylaxis, the oral cavity can be affected by viral pathogens. The most common is reactivation of HSV type 1 infection, which occurs in 65 to 90 percent of seropositive patients receiving high-dose chemotherapy followed by HCT [44].
Infection with HSV should be considered in the differential diagnosis of any patient who presents with mucosal vesicles or unusually painful oral ulcerations after chemotherapy, particularly if candidiasis is not clinically evident. Compared with the oral lesions typically associated with mucositis, the erosions associated with HSV reactivation are more atypical, irregular, and shallow, with a high degree of symptoms, with lesions more likely to present on the keratinized (ie, gingiva, tongue dorsum, hard palate) as compared with nonkeratinized mucosa. A swab of one of the lesions can be sent for viral culture; HSV is usually isolated within 72 hours. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)
Particularly among patients who are HSV-1 seropositive with moderate to severe mucositis, empiric antiviral therapy (ie, parenteral or oral acyclovir, or oral valacyclovir) can be initiated while awaiting culture results [44]. In studies involving immunocompromised hosts with mucocutaneous HSV infection (but not limited to those undergoing chemotherapy), the administration of acyclovir (250 mg/m2 intravenous [IV] every eight hours) for seven days produced significantly shorter periods of viral shedding, more rapid lesion healing, and decreased pain [45,46].
Antiviral treatment for HSV infection and prophylaxis for HCT recipients are discussed in detail elsewhere. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults" and "Prevention of infections in hematopoietic cell transplant recipients", section on 'Antiviral prophylaxis or pre-emptive therapy'.)
Management
Prophylactic oral care — For most patients we suggest prophylactic oral care during systemic anticancer treatment, including a comprehensive oral examination before treatment initiation. This recommendation is consistent with joint updated guidelines from the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO) [47,48] and the European Society of Medical Oncology (ESMO) [49].
●Prophylactic oral care – A comprehensive oral examination before the initiation of cancer therapy is desirable for all patients if feasible [31]. A program of aggressive preventive oral care appears to diminish the incidence of all oral complications of chemotherapy, although the available data on the benefits for prevention of oral mucositis are limited [50-54]. As an example:
•A benefit for weekly prophylactic oral care (teeth surface cleaning, scaling, and tongue cleaning) was shown in a small randomized controlled trial conducted in 169 women with metastatic breast cancer treated with everolimus [54]. Fewer patients who received prophylactic oral care had grade 2 or worse mucositis (34 versus 54 percent), and fewer had everolimus dose reduction because of a severe adverse effect (22 versus 32 percent), the most common of which was stomatitis.
•However, all studies examining the prophylactic benefit of oral care protocols have major flaws, and a 2019 systematic review by the MASCC/ISOO concluded that no guideline was possible regarding the use of professional oral care to prevent oral mucositis in patients undergoing systemic anticancer therapy [47]. Nevertheless, an expert guideline panel also concluded that, despite the lack of data, dental evaluation and treatment prior to cancer therapy are desirable to reduce the patient's risk for local and systemic infections from odontogenic sources [48].
Pretherapy oral hygiene protocols should include scaling and root planing, caries treatment, and endodontic therapy, if needed. In cases of severe odontogenic pathology, tooth extraction should be considered.
●Pulpoperiapical disease – Periapical radiolucencies may represent pulpoperiapical dental infection, especially in the presence of caries. However, these radiographic lucencies can also be associated with other noninfectious conditions, such as postendodontic healing of a treated infection in which the bone does not fill back in or, rarely, leukemic infiltrates at dental root apices [7]. Thus, the incidental finding of an asymptomatic periapical radiolucency requires no specific prechemotherapy intervention [55,56]. Dental or endodontic therapy should be pursued only in patients with signs and/or symptoms that are consistent with acute periapical infection [7].
●Periodontal disease – Pretherapy dental treatment is often recommended to eliminate potential sources of odontogenic infection. However, few outcome-oriented trials have been conducted that support prechemotherapy treatment of chronic periodontal disease [34]:
•In one trial, 166 patients were randomly assigned to limited or intensive oral hygiene care to prevent mucositis during high-dose therapy and HCT [57]. Patients receiving intensive oral care had statistically significant (though clinically unimpressive) benefits in the incidence (85 versus 93 percent) and duration (17 versus 19 days) of moderate or severe mucositis.
•The effectiveness of a preventive oral protocol was evaluated in a prospective, controlled study of 96 children (age 1 to 16 years) with acute lymphoblastic leukemia [58]. Compared with the control children who only received treatment for dental complications rather than prophylaxis, the children in the prophylactic group had improved oral hygiene and a decreased incidence of mucositis and oral candidiasis.
•On the other hand, in a retrospective review of 58 patients undergoing allogeneic or autologous HCT for a variety of malignancies, there was no significant difference in the incidence of infection, mucositis, or post-transplant survival in the group who underwent intensive dental evaluation and treatment pretransplant (n = 36), compared with those who did not [59].
•A prospective pilot trial was conducted at the University of Chicago in which 48 consecutive adults with hematologic or solid malignant neoplasms were assessed for periodontal health prior to chemotherapy, and no pretherapy dental treatment was given to patients with chronic dental disease [60]. Of the 21 who had severe chronic periodontal disease, only two developed acute periodontal infection following chemotherapy, both of whom were managed with antibiotic therapy. In neither case was there interference with chemotherapy or an adverse effect on oncologic outcomes. The authors concluded that patients with chronic dental pathology can safely proceed with chemotherapy without dental intervention as conversion of chronic dental disease to an acute state during chemotherapy occurs infrequently.
If an intertherapy dental infection does arise, it can usually be managed effectively without interrupting therapy or adversely affecting oncologic treatment outcomes. An exception is patients undergoing allogeneic HCT where the additional use of immunosuppressive medications adds additional risks. All efforts should be made to correct any ongoing dental issues prior to proceeding with transplantation.
Because chronic periodontal disease is associated with a substantial microbial burden within the periodontal pocket, it should be suspected as a focus of infection in febrile neutropenic patients [7]. Invasive manipulation of the soft tissues prior to chemotherapy appears to have no adverse effect on the subsequent development of fever or bacteremia, although instrumentation should be avoided during periods of neutropenia [61]. (See "Overview of neutropenic fever syndromes".)
●Tooth extraction – Tooth extraction is commonly recommended prior to therapy for patients with severe periodontal disease, and for those with nonrestorable teeth, necrotic teeth, teeth with periapical infection in which endodontic therapy is not feasible, or partially erupted third molars [7]. Pretherapy tooth extractions can be safely performed without significant risk of postextraction complications [62,63]. However, recommended guidelines include performing extractions at least 10 days prior to chemotherapy, minimizing tissue trauma during the procedure, and obtaining primary closure of the wound without the use of hemostatic packing agents. Platelet transfusion should be considered prior to the procedure if the platelet count is less than 50,000/microL [64].
If tooth extraction is emergently needed in the setting of severe neutropenia (ANC less than 500 to 1000/microL), antibiotic prophylaxis that provides appropriate coverage for Gram-positive and anaerobic organisms (eg, clindamycin 600 mg prior to the procedure, followed by a postextraction course of antibiotics) is adequate for most patients. Severely immunocompromised patients or those with extensive prior antibiotic exposure may benefit from broader-spectrum antibiotic coverage.
Issues related to invasive dentoalveolar procedures in patients who are receiving therapy with antiresorptive agents (ie, bisphosphonates, denosumab) and angiogenesis inhibitors for advanced cancer are discussed elsewhere. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Dentoalveolar surgery' and "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Prevention'.)
Patients receiving chemotherapy — A number of strategies have been employed to prevent or minimize chemotherapy-induced mucositis [3]. Although the quality of evidence derived from randomized trials is limited [65], updated evidence-based clinical practice guidelines developed by the MASCC/ISOO identified oral cryotherapy, palifermin, and photobiomodulation as beneficial in select clinical settings, as discussed below [48].
Preventive treatments that may be beneficial
Oral cryotherapy — For patients receiving bolus FU-containing chemotherapy we recommend oral cryotherapy (ice chips swished around the mouth for 30 minutes). We also suggest the use of oral cryotherapy in patients receiving high-dose melphalan chemotherapy regimens as preparation for autologous HCT. The use of oral cryotherapy in patients receiving other high-dose chemotherapy regimens as preparation for HCT is reasonable given the low toxicity and low cost; however, there is less evidence for benefit.
●Techniques – Most patients achieve cooling of the oral mucosa through intraoral administration of ice chips during chemotherapy administration. This is a cost effective and proven beneficial treatment. Another alternative is use of the Cooral intraoral cooling system. However, this is a more complex and more expensive alternative that is not necessarily more effective or better tolerated than ice chips.
The Cooral system is a fitted device that is shaped and dimensioned to cool the gums, cheeks, tongue, palate and base of the mouth by circulating chilled water continuously within a closed channel [66]. The Cooral system was directly compared with intraoral administration of ice chips in a phase III trial involving 172 patients beginning high dose chemotherapy prior to autologous HCT for multiple myeloma or lymphoma [67]. Each cooling method was started 30 minutes before the chemotherapy infusion, and continued for 30 minutes after completion. Oral mucositis was quantified by an oral mucositis assessment scale (OMAS; a composite score graded 0 to 3 for severity of ulceration, and 0 to 2 for erythema; total score range 0 to 5). Following treatment, oral mucositis of any grade developed in 44 percent of the entire cohort (76 of 172) and was much more frequent (81 versus 38 percent) and more severe (50 versus 14 percent) in those with lymphoma rather than myeloma. Within the entire study cohort, there was no significant difference between the two cooling methods in peak oral mucositis (OMAS 0.99 versus 1.24 for the cooling device and ice chips, respectively, p = 0.351). However, when the analysis was limited to the 26 lymphoma patients, use of the intraoral cooling device was associated with lower peak OMAS score (1.77 versus 3.08, p = 0.047). Secondary outcomes (tolerability, pain score) also favored the intraoral cooling device.
●Fluorouracil-containing regimens – Stomatitis is a major dose-limiting toxicity of FU when it is administered as a short-term bolus, particularly using a monthly, rather than weekly, schedule of administration (the so-called Mayo regimen). Mucositis is less of a problem in patients who receive infusional FU-containing regimens. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Treatment-related toxicity'.)
Because FU has a short plasma half-life, it was postulated that oral cryotherapy around the time of drug administration might induce local vasoconstriction, thereby reducing exposure of the oral mucosa to FU and decreasing the incidence and/or severity of mucositis.
Several controlled trials provide evidence for the benefit of oral cryotherapy in patients receiving bolus FU [68-71].
•A Cochrane review of five trials totaling 444 individuals undergoing treatment with FU concluded that oral cryotherapy probably reduces the severity of oral mucositis of any severity (relative risk [RR] 0.61, 95% CI 0.52-0.72) and the incidence of severe oral mucositis (RR 0.4, 95% CI 0.27-0.61). The number needed to treat to prevent severe oral mucositis in one additional person was six (95% CI 5-9) [72].
•A 2020 systemic review conducted by MASCC/ISOO, which included seven trials of chemotherapy using bolus FU, concluded that there was sufficient evidence to recommend this practice, but that no recommendation could be made as to benefit in the setting of continuous-infusion FU or other conventional-dose chemotherapy regimens given the paucity of data [73].
The optimal duration of cryotherapy was addressed in another randomized trial of 178 patients receiving leucovorin-modulated bolus FU [74]. No additional benefit was seen with 60, as compared with 30, minutes of cryotherapy.
Clinical practice guidelines from several groups recommend the use of oral cryotherapy (ice chips swished around the mouth for 30 minutes) in patients receiving bolus FU-containing regimens [48,49,75]. However, bolus FU regimens are not commonly used in the clinic because of their less favorable toxicity profile, as compared with infusional regimens. The benefit of cryotherapy in patients receiving infusional FU-containing regimens is unknown. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Treatment-related toxicity'.)
●Conditioning regimens for autologous HCT – Although data are more limited, cryotherapy may also be effective in preventing severe oral mucositis in patients receiving high-dose melphalan or other high-dose chemotherapy regimens as conditioning for autologous hematopoietic cell transplantation (HCT); most of the data are in patients undergoing high-dose melphalan [76-80], but there is likely to be benefit with other regimens as well [81,82]:
•The Cochrane review cited above included five studies, totaling 270 patients [72]. The authors concluded that oral cryotherapy might reduce oral mucositis of any severity (RR 0.59, 95% CI 0.35-1.01), but there was uncertainty surrounding the effect estimates; the 95 percent CI ranged from two patients needed to treat to benefit one additional person, to 111 needed to treat in order to harm one additional patient [72]. On the other hand, severe oral mucositis was probably reduced (RR 0.38, 95% CI 0.20-0.72).
•A 2020 systematic review of five trials conducted by MASCC/ISOO concluded that the data were sufficient to recommend cryotherapy for the prevention of oral mucositis in the setting of autologous HCT using high-dose melphalan [73].
Year 2020 clinical practice guidelines from the MASCC/ISOO recommend the use of oral cryotherapy for patients undergoing autologous HCT when high-dose melphalan is used [48]; however, a guideline from ESMO is a "suggestion" rather than a "recommendation" [49]. (See "Early complications of hematopoietic cell transplantation".)
The optimal cryotherapy regimen/schedule is unclear, but results seem to be better if the oral cavity is kept cool continuously. In a randomized trial of 160 individuals receiving busulfan/cytarabine conditioning regimens prior to allogeneic HCT, continuous oral cryotherapy from the beginning of the conditioning regimen infusion until the end or continuous cryotherapy from the midpoint of the conditioning regimen infusion until the end both resulted in a lower incidence and severity of mucositis compared with twice-daily application for 15 minutes each during the period of conditioning [81].
We suggest beginning oral cryotherapy 15 minutes prior to, and continuing through the entire duration of, the chemotherapy infusion.
The clinical presentation, prevention, and management of oral mucositis after HCT are discussed in more detail elsewhere. (See "Early complications of hematopoietic cell transplantation", section on 'Oral mucositis'.)
Palifermin — We suggest palifermin to prevent oral mucositis in patients undergoing autologous HCT with a preparative regimen containing total-body radiation, an approach that is consistent with updated guidelines from MASCC/ISOO and other expert groups. While the use of palifermin to prevent oral mucositis in patients undergoing autologous HCT using any preparative regimen with a high risk of significant mucositis is reasonable, the modest benefit seen with this agent must be balanced against its expense, the lack of benefit in preventing irritation of the rest of the gastrointestinal (GI) tract, and the lack of efficacy in other settings, such as allogeneic HCT and induction therapy for acute leukemia. (See "Early complications of hematopoietic cell transplantation", section on 'Oral mucositis'.)
For patients who develop severe (grade 3 or worse) mucositis during treatment with an FU- or doxorubicin-based chemotherapy regimen, we suggest dose reduction for subsequent chemotherapy cycles rather than prophylactic IV palifermin. While palifermin could be considered in this setting, the drug is expensive, may not be reimbursed for this off-label use, and there are no data demonstrating that outcomes are better as compared with dose reduction.
Palifermin is a recombinant keratinocyte growth factor that stimulates proliferation and differentiation of epithelial cells, including those of the GI tract [83]. The efficacy of prophylactic IV palifermin is supported by the following data:
●Benefit was initially shown in a double-blind, placebo-controlled multicenter trial in which 212 patients undergoing autologous HCT for hematologic malignancies (with a preparative regimen [fractionated total-body irradiation (TBI), etoposide, and cyclophosphamide] known to be associated with a high incidence of mucositis) were randomly assigned to receive either palifermin (60 mcg/kg per day) or placebo for three days before and three days following stem cell infusion [84,85]. Significantly fewer patients receiving palifermin had grade 3 or 4 mucositis (63 versus 98 percent with placebo), and the duration of mucositis was shorter (median six versus nine days). These benefits were associated with significantly less use of opioid analgesics and total parenteral nutrition support.
Largely as a result of these data, palifermin was approved by the US Food and Drug Administration (FDA) to decrease the incidence and severity of severe oral mucositis associated with hematologic malignancies in patients receiving myelotoxic therapy in the setting of autologous hematopoietic stem cell support (when the preparative regimen is expected to result in mucositis grade 3 or worse in most patients).
●A systematic review of five randomized trials conducted by the MASCC/ISOO expert group [86] concluded that palifermin was effective in preventing oral mucositis in patients undergoing autologous HCT that included TBI [85,87-89], but one trial did not show benefit for patients undergoing autologous HCT without TBI [90].
Clinical practice guidelines, including those from MASCC/ISOO, ESMO, the American Society of Clinical Oncology (ASCO; from 2008), and the National Comprehensive Cancer Network (NCCN; from 2008) recommend the use of prophylactic palifermin in patients with hematologic malignancies who are undergoing autologous HCT using preparative regimens that include TBI [48,49,75,91]. However, since radiation-based conditioning regimens have largely been replaced with chemotherapy-only-based regimens followed by autologous HCT, the use of palifermin is relatively low. (See "Early complications of hematopoietic cell transplantation".)
Benefit of palifermin for prevention of oral mucositis in other settings is less certain:
●A randomized trial in the setting of allogeneic HCT failed to show any benefit for prophylactic use of palifermin (incidence of grade 3 or 4 oral mucositis 81 versus 73 percent with placebo) [92].
●Similarly, a randomized placebo-controlled trial of palifermin in 160 patients undergoing induction chemotherapy for acute myeloid leukemia with idarubicin, high-dose cytarabine, and etoposide found no significant difference in the rate of grade 3 or 4 oral mucositis (the primary endpoint) in the palifermin group (4 versus 10 percent), a finding that was attributed to the lower-than-expected rates of mucositis in the control group [93]. While there was a significantly lower rate of grade 3 and 4 GI adverse events (diarrhea, vomiting, oral mucositis) overall with palifermin, this was mainly due to a reduction in severe diarrhea.
●Two of three randomized trials suggest benefits from palifermin among patients receiving less intense chemotherapy regimens (including ifosfamide plus high-dose doxorubicin and FU-based chemotherapy for colorectal cancer) [94-96].
●A Cochrane review of six trials of HCT (five autologous [one with unpublished data], one allogeneic [84,87,90,92,97,98]) and the four trials conducted in patients receiving chemotherapy alone for other indications [93-96] came to the following conclusions [99]:
•There might be a reduction in the risk of moderate to severe oral mucositis in adults receiving HCT after conditioning therapy for hematologic cancers (RR 0.89, 95% CI 0.80-0.99, low-quality evidence). However, the level of benefit is uncertain because of multiple factors in this population, including whether or not TBI was used and whether the transplant was autologous or allogeneic.
•It is likely that there is a reduction in the risk of moderate to severe oral mucositis in adults receiving chemotherapy alone for mixed solid and hematologic cancers (RR 0.56, 95% CI 0.45-0.70, moderate-quality evidence).
●A 2020 systematic review by an expert panel of the MASCC/ISOO concluded that no guideline recommendation was possible regarding the benefit of palifermin in individuals undergoing chemotherapy outside of the setting of HCT.
Photobiomodulation (low-level laser therapy) — The use of photobiomodulation (low-level laser therapy) to prevent oral mucositis in patients undergoing HCT conditioned with high-dose chemotherapy, with or without TBI, may be helpful and is recommended in updated guidelines from the MASCC/ISOO. Specific protocols are endorsed by MASCC/ISOO (table 3). However, in most parts of the world, photobiomodulation is rarely used in clinical practice. It requires expensive equipment and specialized operator training, is limited to centers capable of supporting the necessary technology and training, and the relative benefits of photobiomodulation versus palifermin in patients undergoing autologous HCT have not been addressed in any trial.
Several controlled trials suggest that pretreatment with an intraoral helium-neon laser (He-Ne laser), a form of low-level laser irradiation, reduces the severity of mucositis in patients undergoing conditioning therapy for HCT [100]. As examples:
●In one study, 30 patients undergoing HCT were randomly assigned to observation or He-Ne laser treatment to the entire oral mucosa prior to myeloablative chemotherapy [101]. Those who received laser treatment had significantly lower cumulative mucositis scores and required significantly less morphine for oral pain; however, there was no difference in the need for parenteral nutritional support.
●In a second trial of 20 patients undergoing HCT, one side of each patient's oral cavity was exposed to the He-Ne laser prior to high-dose chemotherapy, while the contralateral side was sham treated and served as the control [102]. The severity of oral mucositis and pain scores were significantly lower for the treated versus the untreated side of the mouth.
A similar degree of benefit has been reported from the application of a low-power diode laser, which is less expensive and easier to use than the He-Ne laser [100,103-108]. As examples:
●In one trial, 38 patients undergoing autologous or allogeneic HCT were randomly assigned to photobiomodulation or control [103]. A significantly higher number of patients undergoing photobiomodulation prior to treatment had oral mucositis that was no worse than grade 2 (95 versus 32 percent in the control group), and fewer developed large (9.1 to 18 cm2) areas of oral ulceration (5 versus 74 percent).
●In a second trial, 70 patients undergoing autologous or allogeneic HCT were randomly assigned to one of two different low-level lasers (650 nm visible red and 780 nm infrared) or placebo [104]. All active photobiomodulation patients received daily direct intraoral laser treatment to the lower labial mucosa, right and left buccal mucosa, lateral and ventral surfaces of the tongue, and floor of the mouth. Treatment with the 650 nm wavelength (but not the 780 nm wavelength) significantly reduced the severity of oral mucositis and pain scores. Photobiomodulation was well tolerated, and no adverse events were noted.
A systematic review of biomodulation for management of oral mucositis in cancer patients concluded that the level of evidence was strong to recommend low-level laser light therapy to prevent oral mucositis in patients undergoing HCT conditioned with high-dose chemotherapy with or without total-body radiotherapy [100]. No guideline was possible for patients undergoing chemotherapy in other settings.
Photobiomodulation has been recommended in consensus guidelines, including those by the MASCC/ISOO and ESMO, to reduce the incidence of oral mucositis in patients receiving a conditioning regimen before HCT [48,49,100]. Two specific protocols have been endorsed in this setting by the MASCC/ISOO (table 3).
The clinical practice guidelines from the MASCC/ISOO also recommend photobiomodulation to prevent treatment-related mucositis in patients with head and neck cancer who are undergoing radiation therapy with or without chemotherapy. This subject is discussed in detail elsewhere. (See "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Laser therapy (photobiomodulation)'.)
Because this therapy requires expensive equipment and specialized operator training, it is limited to centers capable of supporting the necessary technology and training. The relative benefits of photobiomodulation versus palifermin in patients undergoing high-dose therapy and HCT have not been addressed in any trial. Because of these limitations, photobiomodulation is rarely used in clinical practice.
Treatments that are not recommended
●Glutamine – Glutamine is a precursor for nucleotide synthesis and an important fuel source for rapidly dividing cells, such as the lining epithelia of the GI tract. It is postulated to facilitate healing of the GI mucosa, following damage by either radiation therapy or chemotherapy.
•Parenteral – Supplementation with parenteral glutamine has been studied in the setting of HCT. There was no evidence of benefit in terms of mitigation of mucositis incidence or severity [109], and updated clinical practice guidelines from MASCC/ISOO recommend against the use of parenteral glutamine to prevent mucositis in patients undergoing HCT [48]. These trials are discussed in detail elsewhere. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Glutamine supplementation'.)
•Oral – There are conflicting data regarding the benefit of oral glutamine supplements for prevention of mucositis:
-Oral glutamine failed to prevent FU-related mucositis in at least two trials of patients receiving standard-dose FU-based chemotherapy [110,111]. However, a trial in children suggested a possible benefit from oral glutamine [112]. One potential explanation for the conflicting results may be that the poor solubility of glutamine may limit bioavailability to the mucosal surface. At least some data support the view that local uptake by the mucosa (provided by swishing of the product in the mouth) may be essential [113].
-An oral suspension formulation of L-glutamine (Saforis) may provide greater bioavailability to the oral mucosa. In a phase III trial, 326 women with breast cancer scheduled to receive an anthracycline and cyclophosphamide-based regimen were randomly assigned to receive Saforis (2.5 g three times a day for 14 days) or placebo for the first cycle, crossing over to the alternate for cycle 2 of treatment [114]. The incidence of mucositis grade ≥2 was significantly reduced in the Saforis group during the first cycle (39 versus 50 percent with placebo), as was the incidence of severe mucositis (grade ≥3, 1 versus 7 percent, (table 2)). Patients receiving Saforis in treatment cycle 1 had a lower-than-expected rate of oral mucositis when crossed over to placebo for treatment cycle 2, indicating a significant carryover effect.
Independent confirmation of benefit is needed before routine use of prophylactic glutamine suspension can be recommended in any setting. A systematic review of the literature on oral glutamine in 2019 considered the evidence in support of oral glutamine to be insufficient, at least for the setting of HCT and solid tumors other than head and neck cancer receiving chemoradiotherapy [115]. Updated 2020 guidelines for the prevention and treatment of oral mucositis from the MASCC/ISOO suggest the use of oral glutamine to prevent oral mucositis in those with head and neck cancer undergoing chemoradiotherapy, but makes no recommendation for other groups [48]. (See "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Management and prevention'.)
At present, there is no commercially available formulation of any oral glutamine suspension that is approved for use in preventing oral mucositis. Saforis has not been approved for marketing by the FDA or any other regulatory agency.
●Calcium phosphate rinse – Benefit for neutral supersaturated calcium phosphate rinse (Caphosol artificial saliva) was suggested in a double-blind, placebo-controlled trial in which 95 patients undergoing HCT were randomly assigned to calcium phosphate rinse plus a topical fluoride versus topical fluoride alone [116]. Patients using the calcium phosphate rinse had a significantly shorter duration of mucositis (3.7 versus 7 days), and less pain and morphine use. Unfortunately, these results were not confirmed in a later randomized trial conducted in 220 children undergoing allogeneic HCT for any indication [117] and in a third trial compared with cryotherapy alone [118]. A year 2019 systematic review from the MASCC/ISOO concluded that no guideline was possible on the utility of calcium phosphate oral rinses for either prevention or treatment of oral mucositis [115], and no recommendation was made in the updated 2020 MASCC/ISOO guidelines for management of mucositis secondary to cancer therapy [48].
●Other approaches – Several other pharmacologic approaches have either failed to show efficacy in controlled studies, or insufficient data are available to assess their benefit [86,119]:
•Allopurinol mouthwash – Allopurinol mouthwashes have been used in an attempt to inhibit the activation of FU to fluorodeoxyuridine monophosphate in mucosal cells. Early reports of benefit [120,121] were not confirmed in a randomized trial [122].
•Propantheline – An anticholinergic agent, propantheline has been used to decrease salivary flow and thereby reduce oral mucosal delivery of etoposide, a drug that is secreted into saliva. In a small, randomized, placebo-controlled trial (n = 12), propantheline was associated with a lower incidence and severity of mucositis [123].
A protective effect of propantheline-induced xerostomia was also suggested in a larger, but uncontrolled, study of 31 patients receiving high-dose etoposide (3000 mg/m2) as a component of the ICE regimen (high-dose ifosfamide, carboplatin, and etoposide) prior to HCT [123]. Although mucositis developed in 29 (90 percent), it was severe in only three (10 percent). The authors inferred benefit based upon a comparison with a published series of 46 patients treated with the same ICE regimen followed by autologous HCT but without propantheline, in which mucositis developed in all patients and was severe in 78 percent [124].
These data are insufficient to recommend the routine prophylactic use of propantheline in any clinical setting.
•Hematopoietic colony-stimulating factors – The possibility that hematopoietic colony-stimulating factors (CSFs) may protect against the development of chemotherapy-induced mucositis was initially raised in a randomized trial that examined the use of prechemotherapy granulocyte CSF (G-CSF) to maintain chemotherapy dose intensity in patients with advanced bladder cancer [125]. Unexpectedly, G-CSF was associated with a significantly lower incidence (11 versus 44 percent) and severity of mucositis. Data from subsequent trials with mucositis as a specific endpoint have been mixed:
-Benefit was confirmed in at least four controlled trials using either subcutaneous/IV G-CSF or granulocyte-macrophage CSF (GM-CSF) in a variety of clinical settings [126-129], but at least one trial was negative in the setting of HCT [130].
However, a 2017 Cochrane review of interventions to prevent oral mucositis found no compelling evidence of benefit for either GM-CSF or G-CSF [99].This conclusion was also echoed in a 2020 systematic review by an expert panel from MASCC/ISOO [86].
-Topical application of CSFs in a mouthwash formulation has been explored in at least three randomized trials, one of which showed benefit [131], and the others, no benefit [132,133]. The use of topical CSFs to prevent radiation-induced mucositis is addressed elsewhere. (See "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Mucositis'.)
Updated MASCC/ISOO clinical practice guidelines specifically suggest not using CSFs (parenteral or topical) to prevent oral mucositis in patients undergoing HCT [48], and we agree with this position.
•Chlorhexidine – The benefit of chlorhexidine mouth rinses remains uncertain. Three randomized trials assessing the effectiveness of chlorhexidine for mucositis prevention in patients receiving chemotherapy have yielded conflicting results [70,134,135]. Two trials, one in patients undergoing HCT [134] and the other in those receiving standard-dose bolus FU plus leucovorin [70], demonstrated a significant decrease in the incidence of mucositis with chlorhexidine mouthwash relative to placebo. The third trial, conducted in patients receiving a variety of mucositis-inducing regimens, did not demonstrate a benefit compared with sterile water mouthwashes [135].
A 2019 systematic review from the MASCC/ISOO concluded that no recommendation was possible for use of chlorhexidine mouthwashes to prevent oral mucositis in any setting, given the conflicting data [47], although the 2020 updated guideline emphasized that this did not exclude other indications for chlorhexidine, such as prevention or treatment of oral infection [48].
•Other – Randomized, placebo-controlled trials have failed to confirm a consistent prophylactic benefit for sucralfate [136-140], prostaglandins [141,142], chamomile mouthwash [143], systemic pilocarpine, systemic pentoxifylline, and antimicrobial lozenges [144] and mouthwashes derived from a variety of medicinal plants [145]. The available data on amifostine are conflicting [146]. None of these agents can be considered useful for the prevention of chemotherapy-associated mucositis [48,147].
The trefoil factor family of proteins comprises a group of GI peptides that are involved in the protection of the mucous epithelium. Benefit from an oral spray containing recombinant intestinal trefoil factor was suggested in a randomized, double-blind, placebo-controlled phase II trial conducted in patients who developed moderate to severe oral mucositis during the first cycle of FU-based chemotherapy for advanced colorectal cancer [148]. Patients who received one of two doses of the recombinant protein had a significantly lower incidence of moderate to severe mucositis during the second chemotherapy cycle (9 to 12 versus 48 percent). Independent confirmation of these results is needed. A 2017 Cochrane review of interventions to prevent oral mucositis concluded that there was no compelling evidence of benefit from human intestinal trefoil factor [99].
Treatment of established mucositis — Treatment of mucositis due to conventional cytotoxic chemotherapy is supportive and aimed at symptom control. It consists of a combination of oral care (including rinses with saline and/or sodium bicarbonate), topical mucosal protectants, and either topical or systemic analgesia. With the exception of topical and systemic analgesia, the evidence supporting benefit for intervention is weak. Updated guidelines from the MASCC/ISOO specifically recommend against the use of sucralfate to treat oral mucositis in patients with a solid cancer receiving cytotoxic chemotherapy, and consider the evidence to be insufficient to prompt a recommendation for any other form of treatment [48]. We agree with this position.
Routine oral care — For patients with established mucositis, routine mouth care, including removal of dentures, atraumatic cleansing, and oral rinses with a weak solution of salt and baking soda (one-half teaspoon of salt and one teaspoon of baking soda in a quart of water), should be performed every four hours. Although the data on saline or bicarbonate rinses for the prevention or treatment of oral mucositis are limited, the MASCC/ISOO expert panel recognized that these inert bland rinses that increase oral clearance may be helpful for maintaining oral hygiene and improving patient comfort [48].
The oral cavity should be rinsed and wiped after meals, and dentures cleaned and brushed often to remove plaque. A soft toothbrush or foam swab (Toothette) cleans teeth effectively but may be too harsh for patients with moderate to severe stomatitis.
Hydrogen peroxide (diluted 1:1 with saline or water) may be used for gentle debridement. Duration of use of hydrogen peroxide should be limited as chronic therapy may delay healing.
The diet should be limited to foods that do not require significant chewing; acidic, salty, or dry foods should be avoided.
Analgesia — Both topical and systemic approaches have been used to manage pain associated with mucositis:
●Topical lidocaine solutions provide pain relief but require frequent administration. In one trial, topical viscous lidocaine (2 percent) was more effective than diphenhydramine and saline, a kaolin and pectin suspension, or placebo [149].
●Topical lidocaine is frequently combined with cleansing and/or coating agents, a mixture that is often referred to as "miracle mouthwash." There is no fixed formulation, and these mixtures are compounded differently by individual pharmacies, most of which have no set formula [150]. Commonly, these mouthwashes consist of astringent/anticholinergic agents (eg, sodium bicarbonate, diphenhydramine), antacids and/or mucosal protective agents (eg, magnesium aluminum hydroxide), and a topical anesthetic (eg, lidocaine). One example consists of viscous lidocaine (50 mL of a 2 percent solution), sodium bicarbonate (100 mL of a 1 mEq/mL solution), and diphenhydramine (50 mL of a 12.5 mg/5 mL solution) in 500 mL normal saline (resultant fluid volume 700 mL) with instructions to swish and expectorate 10 to 15 mL four to six times per day. Another type of "miracle mouthwash" consists of a mixture of equal parts of viscous lidocaine, diphenhydramine, and magnesium aluminum hydroxide (Maalox).
A commercially available preparation that includes both lidocaine and diphenhydramine plus a variety of coating agents is First Mouthwash BLM (swish and expectorate 10 to 15 mL four to six times daily).
Notably, a systematic review of the management of oral mucositis concluded that there was no evidence supporting the use of mixed-medication mouthwashes for treatment of chemotherapy- or radiation-induced mucositis [151]. Patients may have adverse effects related to the diphenhydramine and lidocaine. Year 2020 guidelines from the Mucositis Study Group of the MASCC/ISOO make no recommendations about the use of mixed-medication mouthwashes [48], while the American Academy of Nursing (AAN) Choosing Wisely statement (in conjunction with the Oncology Nursing Society [ONS]) explicitly recommends against their use [152]. Instead, frequent and consistent oral hygiene with a soft toothbrush and use of a homemade salt-and-soda mouth rinse (one teaspoonful each of salt and sodium bicarbonate in a liter of water) can be used.
●Topical application of morphine sulfate (0.2%, 2 mg/mL in water, 15 mL swish for two minutes and expectorate) may shorten the duration and intensity of mouth pain, even in the absence of significant systemic absorption. One study of 26 patients who had chemoradiotherapy for head and neck cancer, which compared a morphine mouthwash versus a mixture of equal parts of viscous lidocaine, diphenhydramine, and magnesium aluminum hydroxide, demonstrated statistically significantly shorter duration and lower pain intensity with the morphine mouthwash [153]. However, most commercially available oral preparations of morphine sulfate contain glycerin, ethanol, or both. These are not suitable for topical application because alcohol can directly injure the mucosa while glycerin can damage tissues because it is hygroscopic. There are no reliable data on topical morphine in other populations. The updated 2020 MASCC/ISOO guidelines suggested this approach be limited to those with head and neck cancer receiving chemoradiotherapy, but a specific recommendation could not be made for other groups [48].
●Topical doxepin rinse (0.5%) can provide clinically significant pain relief in patients with mucosal damage from a variety of cancer treatments [154]. Although the year 2014 MASCC/ISOO guideline suggested in favor of doxepin mouthwash [155], in 2020, this was changed to "no guideline possible" [48] based on the results of an updated systematic review in 2019 [147].
●Pain may be severe enough to require systemic oral or parenteral opioids. Morphine is recommended as the opioid of first choice for patient-controlled analgesia [156]. The oral route is preferred if the patient can swallow. Another option that is suitable for patients who cannot swallow is transdermal fentanyl. (See "Cancer pain management with opioids: Optimizing analgesia".)
Particularly for severe mucositis in the setting of HCT, patient-controlled analgesia using morphine with appropriate lock-outs is recommended so that pain medications can be delivered in a timely manner in hospitalized patients, especially those undergoing HCT [48,155]. Typically, both a basal rate and intermittent bolus administrations of narcotics are required to achieve adequate analgesia.
Treatments of uncertain benefit
●Mucosal protective agents – A variety of mucosal-protective agents have been used to protect the mucosal surfaces of the oral cavity, including Gelclair, Orabase, Episil (a patented mixture of soy phospholipid [lecithin] and glyceryl dioleate that forms a bioadhesive barrier), topical kaolin/pectin, oral antacids, and propolis (a resinous substance that is used in many parts of the world as a mouthwash) [145,157]. There is little, if any, evidence from adequately powered randomized trials to support benefit from any of these preparations, and two 2020 systematic reviews from expert MASCC/ISOO panels concluded that no guideline was possible [119,147].
As an example, Gelclair is a bioadherent oral mucosal barrier gel containing (according to the FDA label) maltodextrin, polyvinylpyrrolidone, and sodium hyaluronate (but no alcohol or anesthetic agent). It provides a physical adherent barrier over mucosal surfaces, thereby shielding oral lesions from the effect of food, liquids, and saliva [158]. A reduction in oral discomfort within five to seven hours of initial treatment was observed in an uncontrolled, open-label study of 30 hospice patients (only three of whom had chemotherapy-related mucositis) [159]. Benefit continued for more than three hours after each dose in most patients.
The manufacturer recommends that the contents of each packet be mixed in one tablespoon of water, rinsed in the mouth for one minute, and expectorated three times daily at least one hour before eating or drinking [160].
●Vitamin E – Two pilot studies suggest more rapid resolution of mucositis with topical vitamin E treatment [161-163]. In one randomized, double-blind, placebo-controlled trial, six of nine patients treated with vitamin E had complete resolution of lesions, compared with only one of nine receiving placebo. Larger confirmatory studies are needed before the topical application of vitamin E can be considered a standard approach.
A 2019 systematic review concluded that no guideline was possible regarding the use of topical vitamin E for treatment of oral mucositis in any clinical setting [115].
●Other treatments – Efforts to limit mucositis progression by blocking the mechanism of chemotherapy-induced toxicity are ongoing, but so far, they have a relatively limited role. Sucralfate (topical, systemic) is not recommended for treatment of oral mucositis-associated patients with solid tumors treated with cytotoxic chemotherapy [136,147,164]. However, mucositis due to methotrexate may respond to allopurinol mouthwash [161,165] or to the systemic administration of folic acid or leucovorin (folinic acid). (See "Major side effects of low-dose methotrexate".)
Patients receiving molecularly targeted agents — The MASCC/ISOO guidelines for management of mucositis secondary to cancer therapy [48] were not intended to apply to individuals who develop mucositis while undergoing treatment with a molecularly targeted agent. These include orally active receptor tyrosine kinase inhibitors that target, among others, the epidermal growth factor and vascular endothelial growth factor receptors, and inhibitors of the mTOR. (See 'Specific anticancer agents' above.)
There are few trials that have explored any treatment, preventive or otherwise, in this setting, and the best approach is uncertain.
Dexamethasone mouthwash — Benefit for a preventive dexamethasone-containing mouthwash in patients treated with mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitors was suggested in the multicenter phase II SWISH trial, in which 92 postmenopausal women with metastatic, hormone-receptor-positive, HER2-positive breast cancer prescribed everolimus (10 mg daily) and exemestane (25 mg daily) all received a daily mouthwash containing dexamethasone, starting on the first day of the first cycle. Patients were told to swish 10 mL of alcohol-free dexamethasone (0.5 mg/5 mL oral solution) for two minutes and spit, four times daily for eight weeks, and not to eat for one hour after using the mouthwash. The incidence of grade 2 or worse stomatitis at week 8 (the primary endpoint) was 2.4 percent, which compares favorably with the rate seen in a historical control group, women with hormone-receptor-positive metastatic breast cancer treated with combined everolimus/exemestane in the phase III, randomized BOLERO-2 trial of exemestane with or without everolimus (33 percent) [166]. Overall, 90 percent of patients reported no need for dietary restriction because of stomatitis. Although hyperglycemia was the most common toxicity with the dexamethasone mouthwash, rates were not significantly higher than those seen in the BOLERO-2 trial without prophylactic dexamethasone. (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy and targeted agents", section on 'Alternative front-line options'.)
Although these results (and others using alternative glucocorticoid-containing oral rinses [167]) are intriguing, the only way to definitively address the benefit of a prophylactic dexamethasone-containing mouthwash in patients receiving mTOR inhibitors is with a properly performed, randomized, placebo-controlled trial.
Case series further support benefit from local and systemic corticosteroid therapy to treat mTOR inhibitor-associated stomatitis [168-170].
Guidelines from expert groups — Consensus-based guidelines from ESMO [49] endorse expert opinion-based recommendations for prevention and treatment of stomatitis related to molecularly targeted agents from at least three groups [168-170], which are summarized as follows:
●Oral care protocols are suggested to prevent mucositis across all targeted therapy modalities. (See 'Prophylactic oral care' above.)
●Patients should rinse their mouths with a bland nonalcoholic sodium bicarbonate-containing mouthwash four to six times a day to prevent stomatitis. The frequency can be increased up to hourly, if necessary, to treat stomatitis.
●Sugarless chewing gum or candy, salivary substitutes, or sialogogues can be suggested to treat oral dryness.
●Adequate pain management (eg, anesthetic mouthwashes such as viscous lidocaine 2 percent, coating agents, or systemic analgesics) should be provided to treat pain from stomatitis. Alternative administration routes, such as transdermal or intranasal routes, may be considered if taking drugs by mouth is painful.
●For ulcers, topical high potency corticosteroids are suggested initially (eg, dexamethasone mouth rinse 0.1 mg/mL in case several locations in the oral cavity are involved and/or it is difficult to reach the ulcerations; clobetasol gel or ointment [0.05%] in case of limited locations and easy-to-approach ulcers). If there is no ulcer resolution, referral to an oral expert for intralesional steroid injection could be considered. For highly symptomatic ulcers or recurrent ulcers, systemic glucocorticoid therapy can be considered as initial therapy to bring symptoms under control quickly (high dose pulse 30 to 60 mg or 1 mg/kg daily oral prednisone or prednisolone for one week, followed by dose tapering over the second week).
Patients receiving immune checkpoint inhibitors — There are no widely accepted preventive strategies. Dexamethasone mouthwash is a first-line treatment for patients who develop mucositis while receiving immune checkpoint inhibitor immunotherapy. This subject is discussed in detail elsewhere. (See "Mucocutaneous toxicities associated with immune checkpoint inhibitors", section on 'Mucosal toxicity'.)
XEROSTOMIA — Although more commonly attributed to radiation therapy exposure, changes in salivary gland function can also be caused by chemotherapy (including doxorubicin, cyclophosphamide, fluorouracil, methotrexate, vinblastine) [7,171,172]. Reduced salivary flow can also result from anticholinergic medications given for therapy-induced nausea or diarrhea (eg, for irinotecan-related early diarrhea) (see "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Irinotecan'). Clinical presentation is variable, with some patients presenting with dry mucous membranes of varying severity, while others complain of excessive saliva with drooling as a result of dysphagia or odynophagia. The major symptoms associated with xerostomia are dry, uncomfortable mucosal tissues and thick, ropy saliva, which may impair speech and swallowing. Affected patients may also complain of dysgeusia [7].
Chemotherapy-related xerostomia is typically reversible, with spontaneous resolution after completion of chemotherapy [7]. Although it can compound other complications, such as mucositis, this self-limiting form of xerostomia has no significant long-term effects on oral health. Therapy is symptomatic (eg, rinsing with saline or the use of commercially available saliva substitutes). Dry, cracked lips can be treated with petroleum lubricants. (See "Treatment of dry mouth and other non-ocular sicca symptoms in Sjögren's syndrome".)
GINGIVAL BLEEDING — Chemotherapy-induced thrombocytopenia can result in spontaneous gingival bleeding, especially if the platelet count falls below 15,000/microL [173]. Poor oral hygiene or minor oral trauma (eg, from poor fitting dentures, over vigorous brushing of teeth) may worsen this condition due to local inflammation. If brushing creates unacceptable tissue trauma or is painful, plaque control can be achieved with regular use of chlorhexidine oral rinses [31].
Gingival bleeding is reported in patients treated with bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor, but is rare [174,175].
Gingival hemorrhage is usually not a serious or life-threatening complication [7]. If significant spontaneous bleeding occurs, gauze soaked in topical thrombin or aminocaproic acid can be locally applied to obtain hemostasis. Alternatively, custom-fitted mouth guards can be fabricated to serve as a stent, with or without the application of hemostatic agents. Biting down on a popsicle may aid in resolving persistent oozing. Platelet transfusions are rarely required, and resolution occurs quickly as the platelet count begins to rise toward normal levels spontaneously.
ALTERATIONS IN TASTE AND SMELL — Transient alterations in taste and smell are common in patients receiving chemotherapy and may lead to reduced appetite, low energy intake, and weight loss [176-180]:
●In two series with prospective assessment of cancer patients undergoing chemotherapy for a variety of cancer types, taste alterations were reported by 70 and 67 percent, respectively [176,177]. In one of the reports, 49 percent reported olfactory changes during chemotherapy [177].
●In another cohort of 87 patients receiving chemotherapy for breast cancer or a gynecologic malignancy, the significant decrease in olfactory and gustatory function during chemotherapy was restored almost completely to normal by three months postchemotherapy [179]. Olfactory function of older patients was affected more than younger patients.
The conventional cytotoxic agents that have been most associated with taste alterations include anthracyclines, cyclophosphamide, methotrexate, platinum agents, taxanes, ifosfamide, irinotecan, oxaliplatin, fluorouracil, and gemcitabine.
Taste alterations have also been reported in patients treated with molecularly targeted agents, with the most common being imatinib, sorafenib, sunitinib, pazopanib, bevacizumab, temsirolimus, everolimus, vismodegib, sonidegib, glasdegib, crizotinib, pertuzumab, and lapatinib [181-191].
Chemotherapy and targeted therapeutics may affect taste by direct taste receptor stimulation due to secretion of the drug in saliva or via gingival crevice fluid (patients frequently describe a metallic or chemical taste when chemotherapy is delivered), or by altering the signal transduction pathways that mediate taste [188]. In some cases, taste changes may persist after drug clearance, presumably due to direct damage to the taste buds [1,192].
The diagnosis and treatment of disorders of taste and smell are discussed in more detail elsewhere. (See "Taste and olfactory disorders in adults: Evaluation and management".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Mouth sores from cancer treatment (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Types of oral complications – Oral complications resulting from systemic anticancer therapy include mucositis, saliva changes, taste alterations, infection, and gingival bleeding. All of these complications can cause pain and/or impair nutrition. (See 'Introduction' above.)
●Mucositis – The principal manifestation of oral toxicity in patients receiving cytotoxic chemotherapy or molecularly targeted agents is mucositis. Risks are highest with bleomycin, cytarabine, doxorubicin, bolus fluorouracil (FU) agents that block signaling through the epidermal growth factor receptor and the fibroblast growth factor receptor, and mechanistic (previously called mammalian) target of rapamycin (mTOR) inhibitors. (See 'Etiology and risk factors' above.)
•Prevention
-For all patients initiating systemic anticancer therapy we suggest prophylactic oral care, including a comprehensive oral examination before the initiation of treatment (Grade 2C). (See 'Prophylactic oral care' above.)
-For patients receiving bolus FU-containing cytotoxic chemotherapy we recommend oral cryotherapy (ice chips swished around the mouth for 30 minutes) (Grade 1A). For patients receiving high-dose melphalan as preparation for autologous hematopoietic cell transplantation (HCT), we also suggest oral cryotherapy (Grade 2B). The use of oral cryotherapy in patients receiving other high-dose chemotherapy regimens as preparation for HCT is reasonable; however, there is less evidence for benefit. (See 'Oral cryotherapy' above.)
-For patients undergoing autologous HCT with a preparative regimen containing total-body irradiation (TBI) we suggest palifermin (Grade 2B). While use of palifermin to prevent oral mucositis in patients receiving other high-risk preparative regimens is reasonable, the modest benefit seen with this agent much be balanced against its expense, the lack of benefit in preventing irritation of the rest of the gastrointestinal tract, and the lack of efficacy in other settings, such as allogeneic HCT and induction therapy for acute leukemia. (See 'Palifermin' above.)
For patients who develop severe (≥grade 3) mucositis during treatment with an FU- or doxorubicin-based chemotherapy regimen, we suggest dose reduction for subsequent cycles rather than prophylactic IV palifermin (Grade 2C).
-Photobiomodulation (low-level laser therapy) may be helpful in patients undergoing HCT conditioned with high-dose chemotherapy, with or without TBI, specific protocols are endorsed by expert groups (table 3). However, photobiomodulation requires expensive equipment and specialized operator training, is limited to centers capable of supporting the necessary technology and training, and the relative benefits versus palifermin have not been addressed in any trial. (See 'Photobiomodulation (low-level laser therapy)' above.)
-Because of high reactivation rates, antiviral prophylaxis is indicated for herpes simplex virus (HSV)-seropositive patients who are undergoing either induction chemotherapy for acute leukemia or receiving high-dose "conditioning" regimens followed by HCT. (See 'HSV reactivation' above.)
•Treatment – Treatment is supportive and mainly aimed at symptom control:
-Patients should remove and frequently clean dentures, perform atraumatic cleansing of the oral cavity, and use oral rinses with a weak solution of salt and baking soda (one-half teaspoon of salt and one teaspoon of baking soda in a quart of water) every four hours. Rinsing with artificial saliva may lessen the duration and severity of mucositis. A soft toothbrush or foam swab (Toothette) cleans teeth effectively but may be too harsh for patients with moderate to severe stomatitis. (See 'Routine oral care' above.)
-Limit diet to foods that do not require significant chewing; avoid acidic, salty, or dry foods. Patients unable to swallow foods or liquids, may require parenteral fluid and/or nutritional support.
-Adequate analgesia can sometimes be provided topically (eg, viscous lidocaine), but many patients require systemic opioids. (See 'Analgesia' above.)
-The benefit of compounded mixtures (such as "miracle mouthwashes") that contain mucosal protective coating agents, often with topical anesthetics, is uncertain, and for most patients we suggest against their use (Grade 2C). (See 'Treatments of uncertain benefit' above.)
-For patients receiving molecularly targeted agents, our suggested approach includes prophylactic oral care protocols including mouth rinses with sodium bicarbonate-containing mouthwashes adequate analgesia, and steroids (topical, intralesional, or systemic) for patients who develop ulcers during therapy. (See 'Patients receiving molecularly targeted agents' above.)
●Xerostomia – Xerostomia is an uncommon complication of chemotherapy. Therapy is symptomatic (eg, rinsing with saline or the use of commercially available saliva substitutes). Dry, cracked lips can be treated with petroleum lubricants. (See 'Xerostomia' above.)
●Gingival bleeding – Gingival bleeding is most commonly caused by thrombocytopenia. If significant spontaneous bleeding occurs, gauze soaked in topical thrombin can be locally applied to obtain hemostasis. Bleeding usually resolves rapidly as platelet counts increase following the hematologic nadir. Platelet transfusions are rarely required. (See 'Gingival bleeding' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jean-Francois Bedard, DMD, and Joseph A Toljanic, DDS, who contributed to earlier versions of this topic review.
61 : Incidence of fever following invasive oral interventions in the myelosuppressed cancer patient.
64 : Dental extraction in the thrombocytopenic patient is safe and complications are easily managed.
