Management and Prevention of Complications During Initial Treatment of Head and Neck Cancer - UpToDate

1/25/2018 Management and prevention of complications during initial treatment of head and neck cancer - UpToDate
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Management and prevention of complications during initial treatment of head and neck cancer
Authors: Thomas Galloway, MD, Robert J Amdur, MD

Section Editors: Marshall R Posner, MD, Bruce E Brockstein, MD, David M Brizel, MD, Daniel G Deschler, MD, FACS
Deputy Editor: Michael E Ross, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2017. | This topic last updated: Jan 11, 2017.
INTRODUCTION — Toxicity from cancer therapy is classified as acute or late based upon 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 the impairment in the ability to breathe, communicate, and maintain an
adequate oral intake. Oral intake is compromised by swallowing problems (dysphagia and odynophagia),
poor taste (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 to toxicity limiting the ability to speak, eat, and breathe, patients can
experience cutaneous toxicity from both radiation and targeted therapy (cetuximab), neurotoxicity from both
commonly used chemotherapy agents (cisplatin) and radiation, and dental complications from the effects of
radiation dose to the mandible/maxilla and salivary glands.
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.)
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Radiation therapy — Most radiation therapy (RT) toxicity can be divided into acute toxicity, which is
largely unavoidable but transient, and late toxicity, which can be minimized but is generally long lasting and in
some instances permanent. (See "Management of late complications of head and neck cancer and its
treatment".)
Acute toxicity is defined as events that happen during RT or within 90 days after the commencement of
treatment. 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 avoid
overtreatment (ie, not treat unnecessarily large target volumes). (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.
Toxicities of particular note in the context of head and neck cancer treatment include the following:
● fluorouracil commonly causes mucositis even when given without radiation. 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 chemotherapy" and "Cardiotoxicity of nonanthracycline cancer chemotherapy agents"
and "Cutaneous side effects of conventional chemotherapy agents", section on 'Hand-foot syndrome
(acral erythema)'.)
● Cisplatin can cause neuropathy during the initial course of therapy, and can be associated with
significant nephrotoxicity and ototoxicity if adequate hydration is not maintained. (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 [1,2]. (See "Infusion reactions to systemic chemotherapy", section on
'Taxanes'.)
● fluorouracil, taxanes, and platinum agents exacerbate the severity and/or duration of radiation-induced
mucositis.
● 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 exacerbates radiation-induced skin reactions within the treatment volume and can also cause
significant cutaneous toxicity outside of the treatment fields [3]. (See "Cutaneous side effects 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 [4]. 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 [5]. 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 RTOG 01-29, the mortality in the HPV positive group was higher for
those patients who were smokers compared with nonsmokers [6]. (See "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 [7].
The etiology of the acute reaction of salivary gland cells is unclear [8-10]. 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 [11]. 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) during treatment. This regimen can refresh the mouth, loosen thick,
tenacious oral secretions, and alleviate pain due to mild mucositis.
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 [12,13]. 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 [14,15]. 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 RT (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 intensity modulated radiation therapy or
conventional RT, with a dose of 60 to 65 Gy [16]. Grade 2 or worse xerostomia was significantly 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 statistically significant 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 [17]. Unfortunately, patient-reported quality of life did not demonstrate a similar improvement.
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 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 [18,19]. 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) [20].
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 chemoradiotherapy is

unclear. Three small randomized trials suggest that amifostine reduces the frequency and severity of
xerostomia [21-23], but one larger trial did not observe a benefit [24].
● The trials demonstrating the efficacy of amifostine in preventing xerostomia used older RT techniques.
One of the eligibility criteria for the pivotal trial required that a minimum of 75 percent of both salivary
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 [25]. 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 [26].
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 [27-29]. Although a small prospective multi-institutional trial has demonstrated the
reproducibility of this technique [29], 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 [28]. 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 [30].
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. (See "Management of late complications of head and neck cancer and its
treatment".)
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 [31].
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 [32]. However, unlike pilocarpine [33,34], phase 3 trials suggest that the
administration of bethanechol during radiation may result in improved salivary flow and decreased xerostomia
complaints [35,36]. 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 [36]. 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 [37,38]. (See "Management of late complications of head and neck cancer and its treatment",
section on 'Hyperbaric oxygen'.)
Acupuncture — Two small randomized trials in patients with nasopharyngeal carcinoma suggest that
acupuncture can decrease symptoms of xerostomia and improve salivary flow rates [39,40]. These initial
results required confirmation. The increase in stimulated whole saliva was not associated with an increase in
the subjective assessment of dry mouth symptoms, but the literature regarding this subject is limited and
subject to considerable bias. (See "Complementary and alternative therapies for cancer", section on 'Pain
control and xerostomia'.)
MUCOSITIS — Mucositis is a frequent severe complication of radiation therapy (RT) and chemoradiotherapy.
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 [41].
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
chemoradiotherapy regimens.
● The TAX 324 trial, in which patients were treated with induction chemotherapy (docetaxel, cisplatin,
fluorouracil) followed by chemoradiotherapy with carboplatin [42], 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 RTOG 0129, conventionally fractionated RT with three cycles of cisplatin, reported
that approximately 40 percent of patients experienced grade 3 or 4 mucositis [43]. 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 'RT 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 chemotherapy".)
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 — Pilot studies using doxepin rinses suggested that this approach temporarily relieves
pain associated with mucositis due to cytotoxic therapy [44].
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 [45]. 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 preliminary report of 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 [46].
In both of these trials, the doxepin evaluation was based upon the administration of a single dose. The
benefit of doxepin 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 preliminary report of 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 [46].
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 chemoradiotherapy were enrolled, but only 78 were available for efficacy analysis [47]. 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.
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 [48].
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; these results have not yet been published [49]. 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 chemoradiotherapy (70 Gy in
35 treatments, combined with cisplatin 100 mg/m2 on days 1, 22, and 43) [50]. 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 [51]. Patients were
randomly assigned to palifermin or placebo weekly during chemoradiotherapy. 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 — Randomized trials have observed that pretreatment with laser therapy can decrease oral
toxicity due to chemotherapy or RT [52-56].
As an example, 221 evaluable patients were randomly assigned to daily laser or sham treatments during a
six week course of chemoradiotherapy for primary oropharyngeal or oral cavity cancers [56].
Chemoradiotherapy 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 chemoradiotherapy (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.
Although these results are encouraging, the mechanism of action is unclear and the potential interaction with
RT needs to be studied. The prophylactic use of laser therapy to prevent RT-induced mucositis cannot be
recommended until its safety and efficacy are verified in a multi-institutional trial.
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, but currently available evidence does not support their
use:
● 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 [57].
● 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 [58,59].
● 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 [60].
● Amifostine – Amifostine 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 [18]. Guidelines from the American Society of Clinical
Oncology (ASCO) do not recommend amifostine to prevent RT-related mucositis [26]. (See 'Amifostine'
above.)
● Phenylbutyrate – Phenylbutyrate mouthwash was compared with a placebo mouthwash in a 36 patient

phase II randomized trial [61]. Results suggested that phenylbutyrate mouthwashes, initiated at the
earliest appearance of toxicity, significantly decreased the severity of oral mucositis.
● Glutamine – Pilot trials using various oral or intravenous glutamine preparations have suggested that
this agent can decrease the incidence or severity of mucositis [62,63]. These results require confirmation
in larger trials. Current guidelines recommend that systemic glutamine not be used for the prevention of
mucositis [57].
● 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 [64-69]. 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 chemoradiotherapy plus G-CSF
compared with those receiving the same treatments without G-CSF [70].
● Zinc sulfate – Preliminary trials suggest that oral zinc sulfate may be beneficial in treating and preventing
mucositis [71-73]. These results require confirmation.
● Manuka honey – A preliminary trial suggested that administration of manuka honey multiple times daily
limited radiation mucositis in patients who received chemoradiotherapy, as compared with a control
group that received chemoradiotherapy alone [74]. A subsequent placebo-controlled trial failed to
demonstrate a similar benefit [75].
DENTAL ISSUES — Dental status has a significant effect on posttreatment quality of life among patients with
head and neck cancer [76,77]. 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 [78].
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 [77]:
● 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.
● 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 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) [79]. (See "Locally advanced squamous
cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section
on 'Epidermal growth factor inhibition' and "Cutaneous side effects of conventional chemotherapy agents"
and "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) 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.
A number of commercially available skin care products can be used during RT to provide lubrication and
protect the skin. These include aloe vera-based gels and water-based lotions. Although such preparations
may provide symptom palliation, none promotes or accelerates healing of radiation-induced dermatitis.
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 [80].
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 [80]. The incidence is probably
significantly higher in patients receiving a full course of RT or chemoradiotherapy, 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 [80]. Dietary counseling
may be of value.
https://www.uptodate.com/contents/management-and-prevention-of-complications-during-initial-treatment-of-head-and-neck-cancer/print?sectio… 10/19
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 [81]. 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 [81].
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: 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 radiotherapy. By contrast, passive motion
devices can generally be instituted early in the postoperative period [82].
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 [83]. A preliminary study suggested that prophylactic antidepressants may have a role in
minimizing the impact of these symptoms, but these observations require confirmation [84]. (See
"Management of psychiatric disorders in patients with cancer", section on 'Prevention'.)
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
● 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). 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.
● 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 to minimize salivary gland toxicity is with highly conformal
radiation therapy (RT) techniques. Planning of RT fields 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 of 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 37.0
GRAPHICS
NCI CTCAE v4.0 mucositis oral
Adverse
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
event
Oral mucositis Asymptomatic or Moderate pain, Severe pain, Life-threatening Death

mild symptoms; not interfering interfering with consequences;
intervention not with oral intake; oral intake urgent
indicated modified diet intervention
indicated indicated
Oral mucositis is characterized by inflammation of the oral mucosa.
NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events.
Reproduced from: Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, June 2010, National Institutes
of Health, National Cancer Institute. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf (Accessed October 22, 2013).
Graphic 60597 Version 7.0
Contributor Disclosures
Thomas Galloway, MD Consultant/Advisory Boards: Varian Medical Systems [Head and neck cancer
(Training course)]. Robert J Amdur, MD Nothing to disclose Marshall R Posner, MD Consultant/Advisory
Boards: Merck [DMC (Pembro)]; Cel Sci [DMC (IL-2 injections)]. Bruce E Brockstein,
MD Consultant/Advisory Boards: Astra Zeneca [Immunotherapy - head and neck and melanoma
(Durvalumab, tremelimumab)]; Bristol Meyers [Melanoma, head and neck cancer (Ipilimumab, nivolumab)];
Novartis [GIST, sarcoma, melanoma (Imatinib, Dabrafenib, trametinib)]. David M Brizel, MD Nothing to
disclose Daniel G Deschler, MD, FACS Nothing to disclose Michael E Ross, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy

Management and Prevention of Complications During Initial Treatment of Head and Neck Cancer - UpToDate

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1/25/2018 Management and prevention of complications during initial treatment of head and neck cancer - UpToDate

Official reprint from UpToDate®

Authors: Thomas Galloway, MD, Robert J Amdur, MD

SALIVARY GLAND DAMAGE AND XEROSTOMIA

● Whether amifostine is effective at diminishing xerostomia in patients receiving chemoradiotherapy is

Mucoadhesive hydrogel — A proprietary mucoadhesive hydrogel (MuGard) has been developed to

● Phenylbutyrate – Phenylbutyrate mouthwash was compared with a placebo mouthwash in a 36 patient

● Colony stimulating factors – Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and

REHABILITATION — Functional rehabilitation is an important component of patient management and can be

● (See "Alaryngeal speech rehabilitation".)

SUMMARY AND RECOMMENDATIONS

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21. Antonadou D, Pepelassi M, Synodinou M, et al. Prophylactic use of amifostine to prevent

Topic 3408 Version 37.0

NCI CTCAE v4.0 mucositis oral

Oral mucositis Asymptomatic or Moderate pain, Severe pain, Life-threatening Death

Oral mucositis is characterized by inflammation of the oral mucosa.

Graphic 60597 Version 7.0

Conflict of interest policy

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