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Management and prevention of complications during initial treatment of head and neck cancer

Management and prevention of complications during initial treatment of head and neck cancer
Literature review current through: Jan 2024.
This topic last updated: Oct 25, 2023.

INTRODUCTION — Toxicity from cancer therapy is classified as acute or late based on its temporal relationship to treatment. Acute toxicity develops during or shortly after the completion of treatment and is usually temporary. Late toxicity presents months to years after the completion of treatment and is often permanent. The term "complication" is used for a treatment toxicity that causes an important medical problem.

This topic will review the care of patients with head and neck cancer during their initial therapy, both to treat acute toxicity and to prevent late complications. The management of late complications is discussed separately. (See "Management of late complications of head and neck cancer and its treatment".)

GENERAL PRINCIPLES

Spectrum of issues — Cancers of the upper aerodigestive tract are in close proximity to organs vital to a patient's quality of life (eg, tongue, larynx, mandible), and they often emanate from such organs. The involvement of these structures with cancer and the steps needed to eradicate the malignancy can cause a wide spectrum of toxicities.

The most basic toxicities are impairments in the ability to maintain adequate oral intake, breathe, and communicate. Oral intake is compromised by swallowing problems (eg, dysphagia, odynophagia, and possible late esophageal stricture), poor taste (ie, dysgeusia), trismus, xerostomia, and mucositis. Respiration and communication can be compromised by bulky tumors, neuromuscular impairment secondary to tumor growth, or an edematous pharynx and/or larynx. In addition, patients can experience acute cutaneous toxicity from both radiation therapy (RT) and targeted therapy (cetuximab), as well as more subacute or chronic toxicity, such as soft tissue necrosis, scarring, and fibrosis.

Other long-term treatment-related sequelae include neurotoxicity from both chemotherapy (eg, cisplatin) and RT, osteoradionecrosis, carotid artery injury, lymphedema, thyroid damage, and dental complications from RT to the mandible, maxilla, and salivary glands. The management of late complications is discussed separately. (See "Management of late complications of head and neck cancer and its treatment".)

The treatment of these tumors is complex and best handled by a coordinated team involving surgeons, radiation oncologists, medical oncologists, dentists, oral surgeons, speech pathologists, physical/occupational therapists, nutritionists, and skilled nurses.

Surgery — Most surgical complications are subsite specific. Common to any of the surgical procedures is the possibility of cosmetic deformities or functional impairment. With the development of soft tissue transfers, advances in surgical techniques, and organ preservation approaches, these are less common than they were in the past.

Nonetheless, major or even minor surgical defects in these areas may be very evident because of their location on the face and neck, resulting in emotional and psychological distress. (See 'Anxiety and depression' below.)

Radiation therapy — Most RT toxicity can be divided into acute toxicity, which is often unavoidable but transient, and late toxicity, which is generally long lasting and often permanent. (See "Management of late complications of head and neck cancer and its treatment".)

Acute toxicity is arbitrarily defined as events that happen during RT or within 90 days after the commencement of treatment, while intermediate to late toxicity develops beyond that point. Severe acute toxicity can evolve into late toxicity.

RT toxicity is governed by multiple factors, including cumulative dose and fractionation schedule, treatment volume, patient genetics (pharmacogenomics), and the use of concurrent systemic therapy. While a sophisticated understanding of dose-response relationships for normal tissues of interest (eg, parotid gland, larynx, pharyngeal constrictors) can reduce late toxicity, efforts to minimize acute toxicity have been less successful. The simplest and most important way to minimize acute toxicity is to deliver RT with precise targeting and timing, thus avoiding unnecessary overtreatment with excessively large target volumes or doses. (See "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations" and "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy" and "General principles of radiation therapy for head and neck cancer".)

Chemotherapy — In general, the complications of chemotherapy given for head and neck cancer are not unique to these patients. The most commonly used drugs include the platinum compounds (cisplatin, carboplatin), fluorouracil, and the taxanes (paclitaxel, docetaxel). Myelosuppression, nausea, and vomiting are significant side effects with all of these agents. The acute and late toxicities of RT are exacerbated when chemotherapy is delivered concurrently [1,2].

Toxicities of particular note in the context of head and neck cancer treatment include the following:

Fluorouracil commonly causes mucositis when given without RT. Fluorouracil is often given by prolonged infusion in head and neck cancer protocols; this regimen increases the incidence of mucositis and diarrhea, as well as cardiotoxicity and acral erythema (also called hand-foot syndrome or palmar-plantar erythrodysesthesia), compared with daily intravenous bolus administration. (See "Oral toxicity associated with systemic anticancer therapy" and "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines" and "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

Cisplatin can cause peripheral neuropathy and ototoxicity during the initial course of therapy, and it is associated with significant nephrotoxicity if adequate hydration is not maintained. Cisplatin also causes myelotoxicity. (See "Cisplatin nephrotoxicity" and "Overview of neurologic complications of platinum-based chemotherapy", section on 'Peripheral neuropathy' and "Overview of neurologic complications of platinum-based chemotherapy", section on 'Ototoxicity'.)

The taxanes can cause an acute allergic reaction during or shortly after drug infusion, in addition to myelosuppression and neurotoxicity. Allergic reactions can usually be prevented by pretreatment with steroids. Fluid retention often occurs with docetaxel, and its onset can be delayed with concomitant treatment with corticosteroids [3,4]. (See "Infusion reactions to systemic chemotherapy", section on 'Taxanes'.)

Cetuximab, hydroxyurea, fluorouracil, taxanes, and platinum agents exacerbate the severity and/or duration of radiation-induced mucositis, and late scarring and fibrosis. (See "Management of late complications of head and neck cancer and its treatment", section on 'Musculoskeletal issues'.)

Cetuximab can cause an acute hypersensitivity reaction, which can be minimized with antihistamines. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Cetuximab'.)

Cetuximab specifically exacerbates radiation-induced skin reactions within the treatment volume and can also cause significant cutaneous toxicity outside of the treatment volume [5]. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'EGFR inhibitors'.)

Smoking cessation — When smoking is continued during and after RT, it can increase the severity and duration of mucosal reactions, exacerbate xerostomia, and compromise oncologic outcome [6]. All patients should receive counseling about the importance of smoking cessation. (See "Overview of smoking cessation management in adults".)

As an example, one study evaluated 115 patients with head and neck cancer who were treated with RT with or without fluorouracil [7]. The 53 patients who continued to smoke during RT had significantly lower rates of complete response and two-year survival compared with the 62 patients who did not smoke or who had quit prior to treatment (45 versus 74 percent and 39 versus 66 percent, respectively). Among nonsmoking patients, mortality rate was influenced by the duration since quitting smoking. Compared with patients who continued to smoke, the death rate was 40 percent lower in patients who had quit less than 12 weeks before and 70 percent lower in patients who had quit more than one year before diagnosis.

Although the epidemiology of head and neck cancer is changing with the emergence of human papillomavirus (HPV) associated oropharyngeal cancer, the importance of smoking cessation has not changed. In an unplanned analysis of Radiation Therapy Oncology Group (RTOG) 01-29, the mortality in the HPV positive group was higher for those patients who were smokers compared with nonsmokers [8]. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

SALIVARY GLAND DAMAGE AND XEROSTOMIA

Acute injury — The salivary glands would be expected to be a late responding tissue with little acute effects because of their slow cellular turnover (60 to 120 days). However, changes in the quantity and composition of saliva that occur shortly after the initiation of radiation therapy (RT) indicate that these glands exhibit both an acute response and a late response [9].

The etiology of the acute reaction of salivary gland cells is unclear [10-12]. These effects are due to irradiation of both the major (parotid, submandibular, sublingual) salivary glands and the minor salivary glands that are scattered throughout the upper aerodigestive tract. Impaired oral intake due to mucositis or altered sensation of taste may also contribute to decreased saliva production. Comorbid conditions and the medications used to treat them may contribute significantly to the risk of both acute and long-term xerostomia. (See 'Mucositis' below and 'Dysgeusia' below.)

Temporary decreased saliva production becomes evident within one to two weeks after the initiation of RT, and permanent reduction can be noted with cumulative radiation doses as low as 10 to 15 Gy to the parotid gland [13]. During and immediately after treatment, patients should be instructed to drink adequate fluids and to rinse and gargle with either a dilute solution of 25 percent hydrogen peroxide and 75 percent water or a weak solution of salt and baking soda several times daily (one-half teaspoon of salt and one teaspoon of baking soda added to one quart of water). This regimen can refresh the mouth, loosen thick, tenacious oral secretions, and alleviate pain due to mild mucositis. In our experience, the addition of timed-release formulations of guaifenesin can make the secretions thinner and more manageable.

Mean radiation doses to the parotid glands greater than 24 to 26 Gy cause permanent damage to the parotid glands, which typically results in more than a 75 percent reduction in salivary gland function [14,15]. The radiation dose response of the submandibular gland and minor salivary glands of the oral cavity is less well defined than that of the parotid, but avoidance of these organs in a way that does not compromise target coverage and oncologic outcome is advised [16,17]. Xerostomia is the most prevalent late consequence of RT for head and neck cancer and can cause significant symptoms as well as contribute to other complications (eg, dental caries, nutritional issues).

Prevention — The use of contemporary conformal RT techniques to minimize exposure of the salivary glands to radiation is the most important factor in the prevention of permanent salivary gland damage. Amifostine and submandibular salivary gland transfer may have roles in appropriately selected patients.

Highly conformal RT technique — The degree of xerostomia depends in large part upon the volume of salivary tissue irradiated. An important benefit of highly conformal RT approaches such as intensity-modulated radiation therapy (IMRT) is decreased irradiation of the salivary glands and, therefore, less long-term damage. (See "General principles of radiation therapy for head and neck cancer", section on 'Intensity-modulated RT' and "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

The importance of minimizing radiation to the salivary glands was demonstrated in the PARSPORT trial, in which 94 patients with pharyngeal cancer were randomly assigned to IMRT or conventional two-dimensional RT, with a dose of 60 to 65 Gy [18]. Grade 2 or worse xerostomia was less common with IMRT at both 12 and 24 months (38 versus 74 percent and 29 versus 83 percent, respectively). There were no significant differences in other toxicities or in tumor control.

Another prospective randomized trial also demonstrated improvements in observer-related severe xerostomia (39 versus 82 percent), stimulated parotid flow rate, and stimulated whole saliva flow rate among patients with nasopharyngeal cancer who were treated with IMRT rather than two-dimensional RT [19]. Unfortunately, patient-reported quality of life did not demonstrate a similar improvement.

It is unclear whether adjustments in the RT treatment volume during radiotherapy can further reduce the risk of xerostomia. A phase III trial that randomly assigned patients with oropharyngeal cancers who were receiving chemoradiotherapy to adaptive radiotherapy (ART) or IMRT did not find a significant decrease in xerostomia [20]. A weekly replanning CT was acquired for patients treated with ART. Anatomical structures were adjusted but the clinical target volume 70 Gy (CTV70) largely was not (even in the setting of a complete imaging response). ART did not improve the primary endpoint of measured salivary flow, patient reported outcomes, or survival, although it increased a secondary endpoint of excretory function of the parotid gland measured using technetium-99m pertechnetate scintigraphy at 12 months (48 versus 41 percent).

Amifostine — Amifostine is an organic thiophosphate that is thought to act by donating a protective thiol group that is a scavenger of free radicals generated in tissues exposed to radiation. Amifostine is the only pharmacologic agent with established efficacy in the prevention of xerostomia. Its role in patient management is uncertain secondary to the concerns listed below. Currently, the routine use of amifostine in patients receiving modern combined modality chemoradiation (CRT) is not justified.

The benefit of amifostine in the prevention of xerostomia was demonstrated in a trial of 315 patients with head and neck cancer who received definitive or adjuvant postoperative RT (60 to 70 Gy in 1.8 to 2.0 Gy daily fractions) without chemotherapy [21,22]. Patients were randomly assigned to intravenous amifostine (200 mg/m2 per day 30 minutes prior to each radiation dose) or no amifostine. Amifostine reduced the incidence of significant acute xerostomia from 78 to 51 percent, and the incidence of significant chronic xerostomia was found to be reduced at up to 24 months of follow-up. Although concerns have been raised that amifostine might impair the anti-tumor efficacy of treatment, a meta-analysis that included data from 1119 patients on 12 trials, 65 percent of whom had head and neck cancer, found that treatment with amifostine was not associated with an increased risk of death (hazard ratio [HR] for death 0.98) [23].

It is important to recognize that the value of amifostine in the contemporary management of patients with head and neck cancer is unclear:

Whether amifostine is effective at diminishing xerostomia in patients receiving CRT is unclear. Three small randomized trials suggest that amifostine reduces the frequency and severity of xerostomia [24-26], but one larger trial did not observe a benefit [27].

The trials demonstrating the efficacy of amifostine in preventing xerostomia used older, nonconformal RT techniques. One of the eligibility criteria for the pivotal trial required that a minimum of 75 percent of both parotid glands receive >50 Gy. Whether the benefits with amifostine extend to patients managed with highly conformal, parotid sparing techniques such as IMRT is unclear. (See 'Highly conformal RT technique' above.)

Cost, the inconvenience of daily intravenous infusion, and side effects (eg, hypotension, nausea and vomiting) have limited the widespread use of amifostine. Subcutaneous amifostine has been proposed as a more convenient, less toxic alternative. However, a phase III study that was not double blinded found that subcutaneous administration did not significantly improve patient compliance or efficacy compared with intravenous dosing, and the intravenous route was associated with better salivary outcomes by some measures [28]. Approximately 25 percent of patients discontinue amifostine prior to the completion of their RT because of toxicity from the drug.

American Society of Clinical Oncology (ASCO) guidelines recommend that the use of amifostine may be considered to reduce the incidence of xerostomia in patients receiving RT only for head and neck cancer [29]. Patients who may benefit from amifostine are those who are undergoing RT without chemotherapy, are likely to be long-term survivors, are at risk for xerostomia based upon RT fields and/or dose, and who are expected to tolerate the added toxicity associated with amifostine administration.

Submandibular gland transfer — Surgical transfer of the submandibular salivary gland from an uninvolved hemi-neck to the submental space prior to radiation can be useful to maintain saliva production in carefully selected patients [30-32]. Although a small prospective multi-institutional trial has demonstrated the reproducibility of this technique [32], it is currently practiced only at select centers.

The reasons for the limited use of this technique seem to be threefold:

It requires an elective operation on the contralateral neck that includes a level I-III dissection that could be construed as an intensification of therapy.

It has never been tested against modern (ie, submandibular and oral cavity sparing) IMRT, an intervention that does not require an additional operation.

There is no billing code for the procedure, potentially discouraging head and neck surgeons.

In a prospective trial, 120 patients were randomly assigned to salivary gland transfer or to pilocarpine during and for three months after RT [31]. The trial was stopped at a planned interim analysis because of the superiority of the surgical procedure. At six months, there was a statistically significant increase in both baseline and stimulated salivary gland flow rates and the amount and consistency of saliva, favoring the salivary gland transfer procedure. A secondary analysis of 69 patients found that patients who received the submandibular salivary gland transfer had significant improvement compared with those given pilocarpine in swallowing and multiple parameters of quality of life through one year following treatment [33].

Key issues for the use of this technique include the ability to avoid irradiating the submental space without increasing the risk of local recurrence, the identification of a submandibular salivary gland not considered to be at risk for containing cancer cells, and the question of performing a surgical procedure on a patient who is to be managed with RT.

Pilocarpine — Pilocarpine stimulates saliva production from residual salivary gland tissue in patients with established xerostomia patients. (See "Management of late complications of head and neck cancer and its treatment", section on 'Pilocarpine'.)

The administration of pilocarpine during RT has been studied as a way to prevent the subsequent development of xerostomia. However, a systematic review of the literature that included 11 randomized trials concluded that oral pilocarpine could be not be recommended to prevent xerostomia in patients receiving RT for head and neck cancer [34].

Bethanechol — Bethanechol is a cholinergic agonist that stimulates salivary gland function by acting on the muscarinic receptor. Similar to other cholinergic agonists, it significantly increases salivation for patients with radiation-induced xerostomia [35]. However, unlike pilocarpine [36,37], phase 3 trials suggest that the administration of bethanechol during radiation may result in improved salivary flow and decreased xerostomia complaints [38,39]. Once bethanechol was stopped after three months, the benefit seemed to be lost. This implies the benefit is due to stimulation of salivary gland tissue receiving lower radiation dose, and not salivary gland protection [39]. The limited post-treatment follow-up in studies supporting the benefit of bethanechol suggests its benefit may be present only when the patient is actively taking the medication. The potential benefit of prolonged use is unknown, and the prophylactic benefit of bethanechol during radiation must be balanced against the lack of data regarding its long-term impact.

Hyperbaric oxygen — Preliminary evidence suggests that hyperbaric oxygen may have a beneficial effect on xerostomia, but these results must be confirmed on a larger scale before such therapy can be recommended [40,41]. (See "Management of late complications of head and neck cancer and its treatment", section on 'Hyperbaric oxygen'.)

Acupuncture — There are limited high-quality data on the use of acupuncture to prevent xerostomia, and further studies are necessary. In randomized controlled trials of patients with nasopharyngeal carcinoma, prophylactic acupuncture reduced symptoms of radiation-induced xerostomia and improved salivary flow rates, with one study showing improved symptoms as early as three weeks that persisted for up to six months [42,43]. However, these data are subject to bias as sham acupuncture was not included in the control arm of one of these studies [42].

MUCOSITIS — Mucositis is a frequent severe complication of radiation therapy (RT) and chemoradiation (CRT). Radiation-induced loss of stem cells in the basal layer interferes with the replacement of cells in the superficial mucosal layers when they are lost through normal physiologic sloughing. The subsequent denuding of the epithelium results in mucositis, which can be painful and interfere with oral intake and nutrition. Chemotherapy can have a similar effect on the mucosa.

Manifestations — Mucositis usually becomes clinically evident during the second or third week of RT. Its incidence and severity depend upon the radiation treatment volume, dose fractionation schedule, and the use of induction and/or concomitant chemotherapy. Some mucositis is experienced by almost all patients [44]. The most effective ways to minimize mucositis are to properly constrain the volumes of normal mucosal tissues within the high dose radiation treatment volumes and to limit concurrent chemotherapy to use in only those patients who are most likely to benefit from this combined modality approach.

Severe mucositis is encountered with both contemporary induction regimens and contemporary concurrent CRT regimens.

The TAX 324 trial, in which patients were treated with induction chemotherapy (docetaxel, cisplatin, fluorouracil) followed by CRT with carboplatin [45], reported that approximately 25 percent of patients experienced grade 3 or 4 (severe or life-threatening) mucositis during treatment (table 1). Chemotherapy dose reduction of fluorouracil in subsequent treatment cycles is indicated for grade 4 mucositis or prolonged grade 3 mucositis.

The standard arm of Radiation Therapy Oncology Group (RTOG) 0129, conventionally fractionated RT with three cycles of cisplatin, reported that approximately 40 percent of patients experienced grade 3 or 4 mucositis [46]. Only 69 percent of patients were administered the full three cycles secondary to toxicity concerns. There was no significant difference in the incidence of acute toxicity in patients who were treated with accelerated RT schedule plus two cycles of cisplatin, and no difference by p16 status (oropharyngeal cancer patients) within the two arms. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Radiation therapy schedule'.)

Management and prevention — Mucositis is managed symptomatically with scrupulous oral hygiene (including optimization of dentition prior to RT), dietary modification, treatment of superinfections, topical agents, and analgesics.

Acidic or spicy foods, sharp foods (eg, chips), caffeine, alcoholic beverages, and alcohol-containing mouthwashes should be avoided in patients receiving RT directed at the upper aerodigestive tract. In addition, secondary bacterial, fungal (eg, oral candidiasis), and viral (eg, herpes simplex virus) infections should be treated with appropriate agents. (See "Oral toxicity associated with systemic anticancer therapy".)

Despite local measures, pain may be significant during and shortly after the course of RT. Long-acting opiates should be used as needed during the treatment period. Long-acting opiates should not be crushed and put in feeding tubes. For patients who cannot swallow oral medication, transdermal fentanyl may provide good pain relief. Short-acting opiates should be used for breakthrough pain. (See "Cancer pain management with opioids: Optimizing analgesia".)

Doxepin rinse — Data evaluating doxepin rinses suggest that this approach temporarily relieves pain associated with mucositis due to cytotoxic therapy [47,48].

In a multicenter, randomized, double-blind, placebo-controlled trial, 155 patients reporting at least a 4 out of 10 pain from oral cavity radiation were given a single dose of doxepin (25 mg in 5 mL water) or a placebo to rinse and spit [49]. They subsequently crossed over to the opposite treatment arm. Pain was graded on an analog questionnaire.

Treatment with the doxepin rinse significantly decreased pain associated with oral mucositis. Despite stinging burning, unpleasant taste, and greater drowsiness with doxepin, more patients elected to continue doxepin rinse after the blinded phase of the trial.

A second phase III trial with a similar design also demonstrated a statistically significant decrease in pain associated with oral mucositis using doxepin rinses compared with placebo [50].

In both of these trials, the doxepin evaluation was based on the administration of a single dose. The benefit of doxepin over a full-dose course of (chemo)radiation is untested and unknown. Its relative value compared with narcotics is unclear since both can cause drowsiness, and its role remains undefined.

"Miracle" mouthwashes — Topical anesthetics may be combined with an antacid suspension and/or diphenhydramine (for local drying effect) with or without nystatin in a "cocktail," commonly referred to as "miracle or magic mouthwash." The specific formulation may vary and may also include steroids and antibiotics; one such cocktail consists of 2 percent viscous lidocaine, diphenhydramine, and Maalox. Other "cocktails" add dexamethasone solution as an anti-inflammatory or add antibiotics such as tetracycline. Care should be advised for patients using rinses containing lidocaine to avoid further trauma to the anesthetized mucosa.

A phase III trial comparing a mouthwash that included diphenhydramine, lidocaine, and an antacid demonstrated a statistically significant decrease in pain associated with oral mucositis compared with placebo [50].

There are many proprietary mouth rinses that are available to alleviate the symptoms of therapy. Care should be exercised in the use of these preparations, as the formulations may vary considerably from one institution to another. The administration of multiple agents represents a "shotgun" approach to management, with limited efficacy, especially when intensive regimens of chemotherapy and RT are being used. Data are insufficient to recommend any particular formulation.

Mucoadhesive hydrogel — A proprietary mucoadhesive hydrogel (MuGard) has been developed to create a palliative barrier over injured mucosa and potentially decrease the pain and soreness associated with radiation-induced mucositis.

In the placebo-controlled, double-blind trial, 120 patients with head and neck cancer who were being treated with CRT were enrolled, but only 78 were available for efficacy analysis [51]. There was a statistically significant reduction in mouth and throat soreness, the primary endpoint of the trial, in those assigned to the mucoadhesive hydrogel compared with placebo.

However, the trial was not conducted with an intent to treat analysis, and there were no differences in the use of percutaneous gastrostomy (PEG) tubes, emergency department visits, or quality of life.

Benzydamine — Benzydamine is a nonsteroidal anti-inflammatory agent that is given as an oral rinse and has topical anti-inflammatory, analgesic, anesthetic, and antimicrobial activity. Studies of its efficacy have had mixed results [52,53].

In a double-blind trial, 145 patients were randomly assigned to benzydamine during RT. Patients using benzydamine had a significantly higher rate of freedom from ulceration (33 versus 18 percent) and a delay in the use of systemic analgesics during conventional (≤50 Gy), but not accelerated fractionation (≥2.2 Gy daily) RT [54]. Based on this and other data, the MASCC/ISOO advocates for the use of benzydamine in patients receiving conventional RT <50 Gy and in those receiving CRT [55].

However, a phase III double-blind placebo-controlled trial failed to confirm these results (NCT00051441). A study report from the corporate sponsor documents that the data monitoring committee recommended closure of the study at the first planned interim analysis secondary to a lack of efficacy of benzydamine when compared with the vehicle oral rinse group [56]. Benzydamine is available in Europe but has not been approved by the US Food and Drug Administration (FDA).

Palifermin — Palifermin, also known as keratinocyte growth factor, may accelerate epithelial restoration. Palifermin was evaluated in two trials in patients treated with RT for head and neck cancer:

In one trial, 198 patients with locally advanced disease were treated with CRT (70 Gy in 35 treatments, combined with cisplatin 100 mg/m2 on days 1, 22, and 43) [57]. Patients were randomly assigned to weekly palifermin or placebo. The incidence of severe mucositis was significantly decreased with palifermin compared with placebo (54 versus 69 percent). The time to onset of severe mucositis and duration of severe mucositis were also improved (47 versus 35 days and 5 versus 26 days, respectively).

In a second trial, 186 patients were treated with adjuvant RT (60 or 66 Gy) and concurrent cisplatin (100 mg/m2 every three weeks) after resection of stage II to IVB head and neck cancer [58]. Patients were randomly assigned to palifermin or placebo weekly during CRT. Palifermin significantly decreased the incidence and duration of severe mucositis compared with placebo (51 versus 67 percent and 4.5 versus 22 days); the time to development of mucositis was prolonged (45 versus 32 days).

However, the role of palifermin in the clinic remains uncertain. In both trials, there was no decrease in chemotherapy delays, interruptions in radiation due to toxicity, or opioid use. Given the considerable cost to the patient, palifermin is infrequently used in routine practice.

Laser therapy (photobiomodulation) — Randomized trials have observed that pretreatment with intraoral laser therapy (ie, photobiomodulation) can decrease the risk of oral toxicity due to chemotherapy or RT, mainly by stimulating tissue regeneration [59-68].

As an example, 221 evaluable patients were randomly assigned to daily laser or sham treatments during a six-week course of CRT for primary oropharyngeal or oral cavity cancers [63]. CRT consisted of 66 Gy of RT in 33 fractions, combined with cisplatin (100 mg/m2) on days 1, 22, and 43. Low level laser therapy was given daily prior to RT five times per week for 45 days. Patients and assessors were blinded to treatment assignment. Laser therapy significantly decreased the incidence of grade 3 or 4 mucositis at the end of CRT (23 versus 69 percent). Laser therapy also decreased average pain scores using a visual analog scale, analgesic usage, and the need for total parenteral nutrition.

We do not routinely use intraoral laser therapy in the definitive management of head and neck cancer given concerns about using the technology in regions anatomically associated with gross tumor [69]. Its application in the adjuvant setting is practice dependent; specialized staff are necessary to maintain the machine, determine the necessary treatment area and duration at each spot, and deliver therapy prior to each RT fraction [68]. Institutions capable of delivering this therapy may use it for prevention of oral mucositis in patients receiving RT alone or concurrent with chemotherapy, as advocated by the Multinational Association of Supportive Care in Cancer (MASCC)/International Society for Oral Oncology (ISOO) [55,68]. Laser therapy should not be used for treatment of established oral mucositis, as data are limited in that clinical setting.

The use of intraoral laser therapy for treatment of mucositis in patients undergoing conditioning chemotherapy for hematopoietic stem cell transplantation is discussed separately. (See "Oral toxicity associated with systemic anticancer therapy", section on 'Photobiomodulation (low-level laser therapy)'.)

Other approaches — A number of other agents have been evaluated to a much more limited extent for their role in the management or prevention of mucositis.

Investigational agents — The following agents remain investigational:

Avasopasem manganese – Avasopasem manganese, a superoxide dismutase mimetic that limits the formation of reactive oxygen species, reduced the risk and overall severity of CRT-induced mucositis in randomized trials [70,71]. The use of this agent remains investigational, and further data are necessary prior to incorporating it into routine clinical practice.

In a double-blind randomized phase IIb study of approximately 200 patients with locally advanced oral cavity or oropharyngeal cancer treated with RT and concurrent cisplatin-based chemotherapy, the use of GC4419, relative to placebo, decreased the oral mucositis incidence (43 versus 65 percent), duration (2 versus 19 days), and grade 4 toxicity rates (16 versus 30 percent) and was well tolerated [70]. Similar outcomes were also seen in preliminary results from a phase III trial (Reduction in Oral Mucositis with Avasopasem Manganese [ROMAN]) [71].

Probiotics – In a randomized, double-blind, placebo-controlled trial of 99 patients with nasopharyngeal carcinoma, administration of probiotics reduced the severity of oral mucositis induced by CRT [72]. These results require confirmation.

Phenylbutyrate – Phenylbutyrate mouthwash was compared with a placebo mouthwash in a small 36-patient phase II randomized trial [73]. Results suggested that phenylbutyrate mouthwashes, initiated at the earliest appearance of toxicity, significantly decreased the severity of oral mucositis. These results require larger scale confirmation.

Glutamine – Oral glutamine preparations may decrease the severity and duration of mucositis when administered during RT [53,74-76]. Its use as prophylaxis for mucositis is suggested by consensus guidelines from the MASCC/ISOO [55,77]. Oral glutamine may be offered at a dose of 10 grams up to three times a day for prevention of mucositis while receiving RT. In a small, randomized, placebo-controlled trial of patients receiving CRT, oral glutamine reduced both maximal mucositis severity and pain scores after approximately five weeks of therapy [76]. The role of intravenous glutamine has been investigated but is not established [78].

Agents not typically used — The use of the following agents is not supported by the available evidence:

Gabapentin – In a double-blind, phase III trial, 58 patients with locally advanced oropharyngeal cancer treated with CRT were randomly assigned to either prophylactic gabapentin (600 mg orally three times a day) or placebo during treatment. In this study, the addition of prophylactic gabapentin did not improve treatment-related oral mucositis symptoms, based on Patient-Reported Oral Mucositis Symptoms (PROMS) scores obtained at baseline, weekly during CRT, and six weeks after completing therapy [79]. Prophylactic gabapentin also did not significantly impact opioid use for pain control compared with placebo.

Sucralfate – Evidence from a systematic review of the literature and one contemporary placebo-controlled trial indicates that prophylactic mouth washing with sucralfate during RT does not reduce the degree of mucositis and is not indicated [55,80].

Antimicrobial lozenges – Infection has been postulated to play a role in the development of mucositis. However, oral lozenges containing combinations of antibacterial and/or antifungal agents failed to decrease the incidence or severity of mucositis in patients receiving RT in phase III clinical trials [81,82].

Iseganan – Iseganan is a synthetic peptide with broad spectrum antimicrobial activity that is available in an oral solution. Iseganan was tested in a large, multi-institutional phase III trial but failed to meaningfully affect the pathogenesis of radiation-induced mucositis [83].

AmifostineAmifostine decreases the incidence of xerostomia in patients receiving RT for head and neck cancer. In the trial establishing the activity of amifostine for the prevention of xerostomia, there was no evidence that treatment prevented mucositis [21]. Guidelines from the American Society of Clinical Oncology (ASCO) do not recommend amifostine to prevent RT-related mucositis [29]. (See 'Amifostine' above.)

Colony-stimulating factors – Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) have been studied to reduce the incidence and severity of mucositis [84-89]. However, the evidence is insufficient to support their use, particularly since one large trial has suggested that there is significantly worse locoregional control and survival in patients with advanced head and neck cancer treated with hyperfractionated RT or CRT plus G-CSF compared with those receiving the same treatments without G-CSF [1].

DENTAL ISSUES — Dental status has a significant effect on posttreatment quality of life among patients with head and neck cancer [90,91]. Patients with head and neck cancer often have poor preexisting dentition and dental health, which may result in increased risks of complications from their cancer treatment, including osteoradionecrosis and infection in particular.

All patients who will be treated with radiation therapy (RT) for head and neck cancer should undergo a comprehensive dental evaluation prior to treatment. The edentulous patient should be evaluated for retained root tips, alveolar hyperplasia, maintenance of oral hygiene, and assessment for prosthodontics.

Indications for tooth extraction prior to RT are compromised teeth in an area that is expected to receive a dose of at least 50 Gy or a tooth that is out of the radiation treatment volume, but has a hopeless prognosis or is symptomatic. Extraction of healthy teeth does not appear to prevent the development of osteoradionecrosis [92].

All indicated extractions and/or restorative work should be completed prior to RT. A delay of approximately two weeks is ideal between extractions and the beginning of RT to permit proper healing. If the extracted teeth are outside of the treatment volumes, treatment may be initiated sooner. An adequate alveoloplasty should be performed to make the mandible/maxilla "denture ready." Primary closure is preferred, if possible. Postponing needed dental extractions of teeth that will be within the treatment volume until after treatment is associated with an increased risk of non-healing and osteoradionecrosis. (See "Management of late complications of head and neck cancer and its treatment".)

The decrease in saliva and changes in its chemical composition induced by cancer treatment can alter the microbial flora of the mouth and increase the risk of subsequent dental caries. (See "Management of late complications of head and neck cancer and its treatment", section on 'Salivary gland damage and xerostomia'.)

RT can result in complete dental destruction if the teeth are not taken care of with a stricter care regime after radiation. Thus, the long-term maintenance of oral hygiene should be initiated in conjunction with cancer treatment [91]:

Fluoride has been shown to decrease the incidence of caries in patients who have received prior RT, and adherence to fluoride treatment is important. There is no evidence to support the use of one fluoride delivery system over another. Patients should continue to use fluoride daily for the remainder of their lives.

The use of chlorhexidine rinse reduces plaque scores, although this can result in tooth staining, increased calculus formation, or altered sense of taste.

Chlorhexidine rinses are used by some dentists and head and neck surgeons to reduce plaque scores after chemoradiation (CRT). Other experts do not offer these rinses due to risks of tooth staining, increased calculus formation, and altered sense of taste.

Long-term follow-up by an experienced dentist should be provided. Clinical circumstances may require routine visits three to four times per year.

RADIATION DERMATITIS — Radiation dermatitis in the treatment field is common during radiation therapy (RT). The spectrum of injury ranges from hyperpigmentation and dry desquamation of the epithelial layers to moist desquamation and skin necrosis. (See "Radiation dermatitis".)

Damage to the skin can be aggravated by chemotherapeutic agents, including cisplatin, paclitaxel and docetaxel, and cetuximab. Concurrent treatment with cetuximab may be particularly important as a cause of severe radiation dermatitis compared with cisplatin. In a trial in which 424 patients with locoregionally advanced head and neck cancer were randomly assigned to RT with or without concurrent weekly cetuximab, an acneiform rash was significantly more common with cetuximab than with RT alone (84 versus 10 percent), and a severe skin reaction was also significantly more common (35 versus 21 percent) [93]. (See "Cutaneous adverse effects of conventional chemotherapy agents" and "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

Prior to initiating RT, patients should be instructed about appropriate skin care and avoidance of exposure to potential chemical irritants. They should also limit direct sun (UV) and wind exposure. Further details on the prevention of radiation dermatitis, including skin care treatments, are discussed separately. (See "Radiation dermatitis", section on 'Prevention'.)

DYSGEUSIA — Dysgeusia is defined as abnormal or impaired sense of taste; the sense of taste may also be affected by impaired olfaction. An altered sense of taste and/or smell may contribute to nutritional difficulties and weight loss [94].

Both chemotherapy and radiation therapy (RT) may impair the sense of taste by their effects on the receptors in the tongue and nasal epithelium. Other factors that may contribute to an altered sense of taste include a bitter taste from chemotherapy drugs, poor oral hygiene, infection, and mucositis.

In a systematic review of the literature, patients treated with chemotherapy only, RT only, and chemotherapy plus RT had dysgeusia in 56, 67, and 76 percent of cases, respectively [94]. The incidence is probably significantly higher in patients receiving a full course of RT or chemoradiation (CRT), with an onset of impairment during the first two weeks. The sense of taste generally improves after completion of therapy, with return to normal or near-normal levels by one year.

Pharmacologic strategies to prevent or improve the sense of taste using zinc supplementation or amifostine have not shown consistent benefit, and these approaches are not recommended [94]. Dietary counseling may be of value.

OROFACIAL PAIN — Orofacial pain is frequent in patients with head and neck cancer. A systematic review of the literature that included over 3000 patients with squamous cell carcinoma of the head and neck found that pain was present in approximately 50 percent of patients prior to treatment [95]. During treatment, approximately 80 percent of patients complained of pain. Although treatment resulted in some improvement, 36 percent of patients still had such symptoms six months after treatment.

The orofacial pain in these patients appears to be multifactorial. Mucositis, which is frequent during radiation therapy (RT) with or without concurrent chemotherapy, contributes to some of the observed worsening of pain during treatment. Other factors that can contribute to orofacial pain include damage from the cancer itself, inflammation, infection, and scarring from surgery or other treatment [95].

Skillful pain management often determines whether or not a feeding tube is required and whether or not treatment can be completed in a timely manner. The general principles of cancer pain management, including the use of both narcotics and coanalgesics, are discussed elsewhere. (See "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)" and "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'General principles of pain management'.)

TRISMUS — Trismus is a condition characterized by limited jaw opening that is generally caused by a combination of spasm, fibrosis, and contraction of the muscles responsible for movement at the temporomandibular joint. Limited jaw opening during therapy is typically secondary to mucositis and pain. For that reason, passive motion devices are generally not used during radiation therapy. By contrast, passive motion devices can generally be instituted early in the postoperative period [96], and lifelong stretching exercises may be beneficial. Patients who cannot acquire a dedicated passive motion device should be encouraged to perform self-administered stretching exercises.

WEIGHT LOSS AND MALNUTRITION — Xerostomia, mucositis, dental issues, abnormalities in taste and smell, and orofacial pain can all contribute to difficulties in maintaining adequate nutrition during and after treatment. The approach to nutritional support in these patients is discussed separately. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Head and neck cancer'.)

REHABILITATION — Functional rehabilitation is an important component of patient management and can be essential for an optimal outcome following treatment. These issues are discussed separately:

(See "Alaryngeal speech rehabilitation".)

(See "Speech and swallowing rehabilitation of the patient with head and neck cancer".)

ANXIETY AND DEPRESSION — Psychiatric complications, particularly anxiety and depression, are common in patients treated for head and neck cancer, and these can have a significant negative impact on quality of life. As an example, in a prospective series of 357 patients with newly diagnosed head and neck cancer, approximately one-third had a major mood disorder at any given time during the first year after diagnosis [97]. Preliminary studies suggest that the use of prophylactic antidepressants or recreational marijuana may minimize the impact of these symptoms, but these observations require confirmation [98,99]. Importantly, patients should avoid smoke inhalation of any kind during and immediately after curative treatment for head and neck cancer. (See "Management of psychiatric disorders in patients with cancer", section on 'Prevention'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

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

Impact of tumor location on toxicity – Cancers of the upper aerodigestive tract are in close proximity to and often emanate from organs that have an important impact on a patient's quality of life (eg, tongue, larynx, mandible, pharynx (figure 1)). This involvement with cancer and its subsequent eradication can cause a wide spectrum of toxicities, including impairment in the ability to breathe, communicate, and maintain an adequate oral intake.

Multidisciplinary management – The treatment of head and neck cancers is complex and best handled by a coordinated team involving surgeons, radiation oncologists, medical oncologists, dentists, oral surgeons, speech pathologists, physical/occupational therapists, nutritionists, and skilled nurses. (See 'Spectrum of issues' above.)

General measures – Optimal management should include the avoidance of treatment breaks whenever possible. Supportive measures should be instituted early in an attempt to avoid breaks. In addition, smoking cessation likely improves oncologic outcome and reduces treatment-related side effects; it should be strongly encouraged. (See 'General principles' above.)

Xerostomia – The most proven means of minimizing salivary gland toxicity is with highly conformal radiation therapy (RT) techniques. Planning RT treatment volumes that avoid the oral cavity and contralateral submandibular gland likely improves patient quality of life in instances where it is oncologically safe. The use of amifostine is not standard. Although amifostine has been shown to decrease salivary gland toxicity with older RT techniques, there are no analyses demonstrating a benefit for amifostine in the setting of contemporary highly conformal RT techniques. (See 'Salivary gland damage and xerostomia' above.)

Mucositis – Mucositis to some degree is unavoidable. Dietary modification (avoidance of spicy and dry foods), narcotic pain medication, repeated exogenous lubrication, and oral hygiene are all recommended. There are many innovative means to limit this symptom. Although data are insufficient to make a recommendation of an optimal specific therapy, we suggest rinsing and gargling at least several times a day with a solution of warm salt water or baking soda solution (Grade 2C). (See 'Mucositis' above.)

Dental issues – Poor oral hygiene should be addressed prior to the initiation of RT. Every patient should see a dentist prior to initiation of therapy and should be using fluoride treatments to preserve any remaining teeth. Dental problems after RT require special attention. Long-term maintenance of oral hygiene should be initiated in conjunction with cancer treatment. (See 'Dental issues' above.)

Nutritional support – The various acute complications of head and neck cancer and its treatment can all contribute to severely impaired nutrition in this patient population. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Head and neck cancer'.)

Other side effects – Radiation dermatitis, dysgeusia, and orofacial pain are common acute effects and should be managed expectantly. (See 'Dysgeusia' above and 'Radiation dermatitis' above and 'Orofacial pain' above.)

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Topic 3408 Version 62.0

References

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