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chemotherapy (CT)
radiation therapy (RT),
hematopoietic stem cell transplantation
(HSCT)
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5.
CT- and RT-related stomatitis
oropharyngeal pain
xerostomia
oral infection
oral chronic graft-versus-host disease
(cGVHD).
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Stomatitis is an inflammation of the mucous
membranes of the oral cavity and oropharynx
characterized by tissue erythema, edema, and
atrophy, often progressing to ulceration.
The clinical significance of CT- and RTrelated stomatitis as a dose- and treatmentlimiting side effect is well appreciated.
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PATIENT-RELATED
Age older than 65 y or younger than 20 y
Gender
Inadequate oral health and hygiene practices
Periodontal diseases
Microbial flora
Chronic low-grade mouth infections
Salivary gland secretory dysfunction
Herpes simplex virus infection
Inborn inability to metabolize chemotherapeutic agents
effectively
Inadequate nutritional status
Exposure to oral stressors including alcohol and smoking
Ill-fitting dental prostheses
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TREATMENT-RELATED
Radiation therapy: dose, schedule
Chemotherapy: agent; dose, schedule
Myelosuppression
Neutropenia
Immunosuppression
Reduced secretory immunoglobulin A
Inadequate oral care during treatment
Infections of bacterial, viral, fungal origin
Use of antidepressants, opiates, antihypertensives,
antihistamines, diuretics, and sedatives
Impairment of renal and/or hepatic function
Protein or calorie malnutrition, and dehydration
Xerostomia
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Risk factors for CT-related stomatitis are
complex, and study results are conflicting.
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continuous CT infusion therapy for breast and
colon cancer [5-FU and leucovorin ]
selected anthracyclines
alkylating agents
taxanes
vinca alkaloids
Antimetabolites
antitumor antibiotics
myeloablative conditioning regimens for HSCT;
RT to the head and neck.
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Children are 3 times more likely than adults
to develop stomatitis because of a higher
proliferating fraction of basal cells.
Individual drug metabolism affects stomatitis
incidence and severity, as seen with patients
who are unable to adequately metabolize
certain CT
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40% of CT patients develop stomatitis,
Half requiring parenteral analgesia that may
lead to treatment modification.
60% are seen in the HSCT setting,
Oral infection, herpes simplex virus (HSV) in
particular, may increase stomatitis severity
a 4 times greater relative risk of septicemia
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asymptomatic erythema and progresses from
solitary, white, elevated desquamative
patches that are slightly painful to large,
contiguous, pseudomembranous, painful
lesions.
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Area
Type of ionizing radiation
volume of irradiated tissue
daily and cumulative dose
duration of RT
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Stomatitis is a dose- and rate-limiting toxicity of
RT for head and neck cancer, and of
hyperfractionated RT and CT that is designed to
improve survival time.
COX-2 plays an amplifying role in RT-related
stomatitis.
Atrophic changes in the oral epithelium usually
occur at total doses of 1,600 to 2,200 cGy,
administered at a rate of 200 cGy per day. Doses
higher than 6,000 cGy place the patient at risk
for permanent changes in the salivary glands.
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depend primarily on salivary changes rather
than on direct irradiation of the teeth.
Direct irradiation of teeth may alter the
organic or inorganic components making
them more susceptible to decalcification or
hypocalcification.
daily fluoride application is necessary
Long-term effects of head and neck RT
1. Soft tissue fibrosis
2. Obliterative endoarteritis
3. Trismus
4. Nonhealing or slow-healing mucosal
ulcerations
5. slow healing of dental extraction sites.
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RT-induced fibrotic changes
 up to 1 year post-therapy, becoming more
serious over time.
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Higher incidences are seen after total doses
to the bone exceed 65 Gy.
The risk of ORN actually increases over time
following RT.
pathologic fracture, infection of surrounding
soft tissues, and severe pain.
time to allow adequate extraction site healing
is 10 to 14 days before start of RT.
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Long use :bisphosphonate therapy
majority required surgical procedures to
remove the involved bone.
Oral candidiasis
angular cheilitis,
may appear as white and removable
chronic hyperplastic (nonremovable)
chronic erythematous (diffuse patchy
erythema).
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Acute GVHD occurs within the first 100 days
after allogeneic HSCT.
Chronic GVHD begins as early as 70 days or
as late as 15 months after allogeneic
transplant.
80% of patients with extensive cGVHD have
some type of oral involvement
Oral infection in cGVHD patients is a risk
factor for systemic infections that are the
primary cause of death in this population
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stomatitis-related pain
Immunocompromised cancer patients with
HSV infections have larger, more painful
lesions as compared with noncancer patients
cGVHD
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effect on the patient's psychological
well-being:
medication usage,
decreased oral intake
use of analgesics and opioids.
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individual's thought process,
self-perception,
reported pain relief,
the personal meaning of the pain.
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The sociocultural dimension includes
demographic characteristics, cultural
background, and family and work roles.
age and pain perception,
intraethnic differences in pain perception
Gender
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Pain control is critical to accomplish to avoid
suffering and psychological distress.
Effective oral pain management is promoted
through open, consistent communication
between and among patient, physician, nurse,
and caregiver.
A comprehensive pain assessment tool?
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Xerostomia
Severity dependent on the radiation dosage and
location, and volume of exposed salivary glands.
Significant xerostomia has not been reported in
patients treated with CT alone.
Xerostomia can affect oral comfort, fit of
prostheses, speech, and swallowing.
Xerostomia-associated enzymes contribute to
the growth of caries (decay)-producing
organisms, and the decrease in quantity and
quality of saliva can be very harmful to dentition
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Pretherapy Dental Evaluation and Intervention
Assessment of the Oral Mucosa
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an experienced dental team
Many health care institution-specific policies
and preventive approaches exist for oral care
for CT and RT patients.
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dental screening at least 2 weeks before
therapy
Oral hygiene
related to several important factors, including
radiation exposure
, type,
portal field,
fractionization,
total dosage
tumor prognosis,
expediency of control of the cancer.
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Careful examination of extraction sites must
be performed before RT commences.
Dental extractions following RT require
collaborations between dental and radiation
oncology team members to minimize the risk
of ORN.
A low incidence of ORN is seen when pre-RT
dental consultation and appropriate
treatment (e.g., extractions) are rendered.
Follow-up
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Assessment of the Oral Mucosa
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The optimal treatment ?
mainly empirical
The only standard forms of care are
pretreatment oral/dental stabilization, saline
mouthwashes, and oropharyngeal pain
management.
oral hygiene
unreliable evidence for the effectiveness of
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allopurinol mouthwash,
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vitamin E,
3. immunoglobulin,
4.
human placental extract
 no single agent completely prevented
stomatitis, suggesting that combined
strategies may be necessary
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A standardized approach for the prevention
and treatment of CT- and RT-induced
stomatitis is essential.
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Chlorhexidine gluconate (Peridex),
Saline rinses,
Sodium bicarbonate rinses,
Acyclovir
Amphotericin B
Ice
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a local anesthetic such as lidocaine or
dyclonine hydrochloride, magnesium-based
antacids (Maalox, Mylanta), diphenhydramine
hydrochloride (Benadryl), nystatin, or
sucralfate
These agents are used either alone or in
various combinations as a mouthwash
formulation.
opioids
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used less commonly include kaolin-pectin
(Kaopectate), allopurinol, vitamin E, betacarotene, chamomile (Kamillosan) liquid,
aspirin, antiprostaglandins, prostaglandins,
MGI 209 (marketed as Oratect Gel), silver
nitrate, and antibiotics
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has shown efficacy in the treatment of
gastrointestinal (GI) ulceration
has been tested as a mouthwash for the
prevention and treatment of stomatitis?
CT?
Sucralfate has also been tested in the head
and neck RT population?
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Gelclair is a concentrated, bioadherent gel
that has received for the management of
stomatitis-related oral pain.
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Benzydamine is a nonsteroidal antiinflammatory drug with reported analgesic,
anesthetic, anti-inflammatory, and
antimicrobial properties.
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‫بتامتازون ‪+‬اب‬
‫هیدروکورتیزون ‪+‬نیستاتین ‪+‬تتراسایکلین ‪+‬دیفن هیدرامین‬
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Vitamin E +
vitamins C and E and glutathione ?
Azelastine may be useful to prevent CTinduced stomatitis
Silver Nitrate +
 Laser?
 Miscellaneous Agents?
diphenhydramine hydrochlor-ide (Benadryl),
saline, sodium bicarbonate, and gentian
violet
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Cryotherapy used to induce vasoconstriction
should be considered for patients receiving
5-FU or melphalan when these agents are
administered during short infusion times.
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Hematopoietic Growth Factors?
Keratinocyte Growth Factors
Antimicrobials
Pharmacologic Modulation
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Recently, palifermin, which is a recombinant
human keratinocyte growth factor, has shown
efficacy in the reduction of oral mucosal
injury related to cytotoxic therapy
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Treatment approaches for oral candidiasis
include Mycostatin (troches), nystatin (liquid
or ointment), or clotrimazole.
Pseudomembranous candidiasis is
successfully treated topically.
Chronic candidiases usually requires much
longer treatment, and it may be necessary
to use oral ketoconazole, fluconazole, or
intravenous amphotericin B.
chlorhexidine mouthwash ?
Allopurinol mouthwash for the prevention and
treatment of 5-FU-related stomatitis
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positive results have led to allopurinol
becoming routine practice.
no protective effect of allopurinol against 5FU-induced stomatitis was seen in a
randomized, double-blind clinical trial
conducted by the NCCTG and the Mayo Clinic.
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RT-induced fibrosis of the masticatory muscles
and/or the temporal mandibular joint may be
prevented or attenuated through early exercises
with trismus appliances posttherapy. Fibrosis of
the masticatory muscles may occur up to 1 year
postradiation; therefore, jaw-opening exercises
should start after oral mucosal healing and
continue for more than 1 year following RT.
Effective exercises in reducing trismus include
the use of tongue depressors taped together 10
to 15 times a day for 10-minute sets.
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Antibiotics and surgical debridement and
curettage.
Hyperbaric oxygen ?
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conservative debridement and antibiotic
therapy.
surgical procedures to remove the involved
bone.
Early diagnosis
pretherapy dental care
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Stomatitis is the principal etiology of most pain
experienced during the 3-week post-BMT time
period.
Stomatitis-related oropharyngeal pain is
multidimensional.
Immunocompromised patients with cancer who
are also HIV develop larger, more painful lesions
Oral pain associated with cGVHD has been
described as severe, with symptoms of burning,
irritation, dryness, and loss of taste has been
reported.
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viscous lidocaine (Xylocaine) or dyclonine
hydrochloride
temporary pain relief
kaolin-pectin, diphenhydramine, Orabase,
and Oratect Gel.
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One large clinical research center uses a
topical formulation that contains lidocaine
viscous 2% (40 mL), diphenhydramine 12.5
mg/5mL (40 mL), and Maalox 10 mg (40 mL)
and prescribes its use every 3 to 4 hours as
needed.
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Severe stomatitis-related oropharyngeal pain
may interfere with hydration and nutritional
intake and affect quality of life. Management
of this oropharyngeal pain may require use of
opioids,
oral transmucosal fentanyl was more effective
than morphine sulfate immediate release in
treating breakthrough pain
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At present, no standard treatment has been
defined for the prevention or treatment of
stomatitis-related oral pain; therefore, it is
essential to continue studies of the
treatments already available and to develop
promising new approaches.
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Oral hygiene regimens that include the use of
water/saline and daily fluoride application
along with brushing teeth at least 3 times
daily may reduce colonization and
proliferation of oral pathogens.
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pilocarpine, 5- and 10-mg doses
amifostine (Ethyol), administered at 200
mg/m2 as a 3-minute intravenous infusion
15 to 30 minutes before each fraction of
radiation.
Artificial saliva, which usually uses
carboxymethylcellulose as a base?
sugarless gum and hard candy
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Conclusion