1. 3. Radiation Effects - Mucosa, Taste, Jaw
Opening
John Beumer III, DDS, MS
Eric Sung, DDS
Division of Advanced Prosthodontics,
Biomaterials and Hospital Dentistry and
UCLA School of Dentistry
All rights reserved. This program of instruction is covered by copyright ©. No
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2. Radiation Effects - Mucosa, Taste, Jaw
Opening
Treatment and Prevention
v Mucosa
v Acute effects
v Mucositis
v Fungal infections
v Management of mucositis
v Taste apparatus
v Late effects
v Mucous membranes
v Muscle
v Skin
v Edema
v Jaw opening
v Dynamic bite openers

3. Radiation Effects - Oral Mucous Membranes
Early changes in oral mucous membranes
v Pathophysiology of oral mucositis (Sonis, 1998,
2004)

4. Pathophysiology- Radiation Mucositis
Sonis model (1998, 2004)
Initiation
l Reactive oxygen species results in
breaks in DNA strands
Primary damage response
l NF-kB
l Upregulation of genes producing
proinflammatory cytokines
Signal amplification
l Colonization of oral bacteria leads to
production of additional cytokines
which lead to more tissue damage
Ulceration
Healing

5. Radiation Mucositis Key - Facts
Presents initially as an erythematous reaction which soon
develops into oral ulcerations covered with pseudomembranes.
Severity dependent upon:
v Clinical treatment volume, dose and fractionation.
v Sites: The less keratinized the mucosa the more severe the mucosal reactions
v More severe in patients presenting with chronic alcoholism and liver cirrhosis
v More severe in patients with insulin dependent diabetes
v Severity may be lessened by a reduction of oral bacterial loads
Mucositis is more severe in patients
.
receiving concomitant chemotherapy.

6. Radiation Mucositis – Key Facts
v It is one of the most clinically
significant side effects of treatment.
v Its frequency and severity limit the
aggressiveness of therapy and may
interrupt or preclude completion of
therapy.
v It has a significant impact on the cost
of care (Peterson et al, 2001).
v There is no effective treatment.
v Palliation of symptoms is the only
possible approach at present.
.

7. Radiation Mucositis – Key Facts
v Incidence – 80% per cent or
more depending upon the
dose per fraction (Vinssink et al,
2003)
v Secondary to radiation
induced mitotic death of the
cells composing the basal
layer of the epithelium (Scully
and Epstein, 1996; Dumbrique et
al, 2000).
v Rarely seen when the dose
per fraction is below 180 cGy
per fraction (Silverman, 2003)
.

8. Mucositis
Oral mucositis begins as an erythematous reaction associated
with the tumor site generally after about 7-10 days of the
therapy. This erythema is accompanied by soreness and a
burning sensation.

9. Mucositis
v The erythematous reaction is followed by ulceration. With conservative
treatment approaches the ulcerations remain confined to the tissues associated
with the tumor volume.
v With more aggressive treatment (ie. Chemoradiation) the mucositis is more
extensive involving normal tissues adjacent to the gross tumor volume.
v With conservative treatment approaches the mucosa re-epithelializes 2-4
weeks following completion of therapy.
If concomitant chemotherapy is employed, twice or
longer the usual time is required for re-epithelization.

10. Mucositis
In most patients the ulcerations remains confined to the tumor
site. After radiation the ulcerations re-epithelialize and become
covered with “normal” appearing oral mucosa.
However, if concomitant chemotherapy is employed these
ulcerations may take several months to heal.

11. Mucositis
Backscatter – Mucositis is particularly localized in this
patient. This results when a metallic crown rests against oral
mucous membrane and is in the path of the radiation beam.
Prevention is easily accomplished by displacing the buccal
mucosa or tongue away from the crown with a stent.

12. Backscatter
Titanium reconstruction plates, implants, trays
and mesh (Schwartz et al, 1979; Mian et al, 1987)
Dose enhancement at the
bone implant interface is
about 15-18%.

13. Backscatter
Irradiation of existing implants
Backscatter- This patient received 6000 cGy postoperatively.
Previously, a fibula free flap had been used to reconstruct a
mandibular continuity defect. Implants were placed at the
same time the fibula was placed.

14. Backscatter
Irradiation of existing implants
Following radiation, the patient developed a dehiscence over the
left implant which eventually lead to exposure of bone. The two left
implants were eventually lost. A piece of bone was sequestrated
and eventually this area became covered with mucosa.

15. Backscatter
Irradiation of existing implants
However, the flap was not lost and
mandibular continuity was maintained.

16. Acute Effects – Oral Mucous Membranes
Patients with compromised oral mucous membranes
secondary to chronic alcoholism with liver cirrhosis or insulin
dependent diabetes and those treated with chemoradiation
may develop more severe mucositis.
A B
In patient “A” virtually all of the epithelium on the soft palate was
lost and therapy had to be interrupted to allow the mucosa to re-
epithelialize. In patient “B” the tongue became depapillated but
therapy was completed without interruption.

17. Acute Effects – Oral Mucous Membranes
Candida albicans infection
During the administration of radiation therapy acute candidiasis can occur
(Ramirez-Amador, etal, 1997).
Topical therapy: It is best managed by nystatin suppositories used as an oral
lozenge (100,000 units per suppository) or by the use of nystatin oral rinse
(100,000 units per cc). If the patient is wearing dentures, they should be
soaked in a nystatin solution daily.
If the patient has difficulty dissolving the lozenges intraorally because
of xerostomia, a nystatin oral suspension is a useful alternative.

18. Acute Effects – Oral Mucous Membranes
Candida albicans infection
Systemic therapy: *Prolonged use of antifungal
v Ketoconazole (200 mg daily agents is discouraged
with food) because of the risk of
v Fluorconozole ( 100 mg daily) developing fungal resistance.
(Silverman, 2003)
Systemic therapy is preferred in the
potentially noncompliant patient.

19. Acute Effects – Oral Mucous Membranes
v Changes in the oral flora during therapy are thought
to intensify radiation mucositis (Ramirez-Amador et
al, 1997).
v Colonization by gram negative bacilli (Spijkervet,
1991) appear to induce more severe mucosal
reactions such as the reaction in this patient.

20. Acute Effects – Oral Mucous Membranes
Management of mucositis during therapy
v At present there is no effective approved
means of reducing the severity of oral
mucositis
v During the past 15 years 1his field has
been the subject of intense study

21. Treatment
Management of mucositis during therapy
Continues to be supportive and symptomatic
v Saline and soda rinses
v Viscous xylocaine
v Systemic analgesics
v Antifungal medications

22. Treatment of Mucositis
Research Approaches
v Radioprotective agents
v Anti-inflammatory agents
v Mucosal decontamination
v Growth factors

23. Treatment of Mucositis
Research Approaches
Radioprotective agents – Free radical and
reactive oxygen inhibitors
v Amifostine
v Benzydamine
v N-acetylcysteine

24. Treatment of Mucositis
Research Approaches
Radioprotective agents – Free radical and reactive oxygen
inhibitors (Antonadou et al, 2002; Buntzel et al, 2002; Sonis,
2004; Law et al, 2007)
v Amifostine
v Benzydamine
v N-acetylcysteine
" These agents act as free radical and ROS scavengers and theoretically
minimize much of the deleterious effects of irradiation on normal cells.
" These drugs are also potent anti-inflammatory agents.

25. Treatment of Mucositis
Research Approaches
Radioprotective agents – Free radical and reactive oxygen
inhibitors (Antonadou et al, 2002; Buntzel et al, 2002; Sonis,
2004; Law et al, 2007
v Amifostine
v Benzydamine
v N-acetylcysteine
" The data is has been contradictory and study designs have been questioned
(Sutherland and Bowman, 2001).
" Concern voiced regarding tumor uptake and impact on tumor response
(Vissink et al, 2003).

26. Treatment of Mucositis
Research Approaches
Mucosal decontamination
v Chlorhexidine – Has not shown to be effective in
reducing the severity of mucositis (Spijkervet et al, 1989;
Epstein et al, 1992; Foote et al, 1994; Dodd et al, 1996;
Adamietz et al, 1998).
v Antibacterial lozenges targeting gram negative bacillus
(combination of amphotericin B, polymyxin, and
tobramycin) have shown some promise in reducing the
severity of mucositis (Spijkervet et al, 1990, 1991;
Symonds et al, 1996; Wijers et al, 2001; Mellroy, 2007)

27. Treatment of Mucositis
Research Approaches
Growth factors
l Keratin growth factor (KGF)
l Granulocyte-macrophage stimulating factor
May promote more rapid healing by
stimulating surviving stem cells but have the
potential of affecting the tumor response

28. Chemoradiation
v Used as an adjunct or concomitantly
v Oral side effects are more severe
• Acute effects
§ Oral mucositis is more severe and generally takes 3 to 8 months to
resolve as opposed to the 2-4 weeks when radiation alone is given.
Some patients are unable to complete therapy because of the side
effects.
§ About one half of the patients need “G” tubes placed in order to make
it through radiation.

29. . Chemoradiation
Late effects
v Incidence of scarring and fibrosis, osteoradionecrosis and
soft tissue necrosis appears much higher when used in
conjunction with CRT. Little data available when used
with IMRT
v Asubstantial number of patients are unable to swallow
after therapy secondary to atrophy and fibrosis
associated with the muscles of the pharynx. These
patients must be fitted with permanent “G” tubes.
v Increasing
number of patients suffer from velopharyngeal
incompetence, velopharyngeal sufficiency and trismus
after chemoradiation secondary to fibrosis and atrophy of
the muscles associated with mastication and
velopharyngeal function.

30. Acute Effects – Taste Apparatus
v Taste acuity is readily affected by tumoricidal doses
of radiation (Sandow et al, 2006; Mirza et al, 2008).
v Dramatically effects the quality of life (Redda and
Allis, 2006
v Changes in taste cells and buds are due to both the
direct and indirect effects of irradiation (Yamashita et
al, 2006).

31. Acute Effects – Taste Apparatus
v Architecture of the taste buds is almost completely
eliminated at 5000 cGy.
v Alterations in taste acuity are first noticed during the second
week of therapy (Conger and Wells, 1969; Conger, 1973;
Silverman et al, 1983).
v Perception of bitter and acid flavors is more susceptible to
impairment than salt and sweet

32. Acute Effects – Taste Apparatus
v Taste generally returns to “near normal” 2-4 following re-
epithelialization if salivary flow is reasonable.
v In patients with severe xerostomia following radiation the
number of buds is decreased, their morphology is altered
and taste may not return to normal.
v Reduction may also be secondary to loss of nerve fibers
innervating the taste buds
v Clinical trials with Zinc supplements have shown promise
(Silverman et al, 1983; Ripamonte et al, 1998; Matsuo et al, 2000)

33. Acute Effects - Olfaction
v Since the olfactory epithelium is high in the nasal
passage and often not within the clinical treatment
volume smell is less affected
v Smell thresholds after radiation exposure are
increased dramatically (Ophir et al, 1988).
v Few if any patients experience complete recovery

34. Late Effects – Oral Mucous Membranes
v Scarring and fibrosis of lamina propria
v Telangiectasia – dilation and coalescence of small venules close
to the surface of the epithelium
v Epithelial layer is thinner and less keratinized
Clinical significance: The oral mucosa is easily traumatized or
perforated. The ulcerations that develop are slow to heal because of the
reduced vascularity and fibrosis of the underlying connective tissue.
Clinical significance: The denture bearing mucosal surfaces are
compromised making tolerance of complete dentures difficult.

35. Late Effects – Oral Mucous Membranes
Scarring and telangiectasia
In most patients scarring and telangiectasia
are confined to the tumor site ( arrow).

36. Late Effects – Oral Mucous Membranes
Scarring and telangiectasia
When the telangiectasias extend beyond the local
tumor volume as in these two patients, it indicates:
v The patient tolerated the radiation poorly.
v The dose to the normal adjacent tissues was brought to the
highest level of tissue tolerance.
v The patient was treated with concomitant chemoradiation

37. Late effects
Muscle wasting and fibrosis
v In patients treated for pharyngeal, soft palate and base of
tongue tumors, fibrosis and muscle wasting of the muscles of
pharyngeal wall and the soft palate responsible for
velopharyngeal closure leads to velopharyngeal insufficiency.
v These changes are more common in patients treated with
chemo-radiation and many patient are unable to swallow after
completion of radiation therapy.

38. Late effects
Muscle wasting and fibrosis
This patient was treated with external beam plus brachytherapy
for a squamous carcinoma of the tongue. The volume of tissue
encompassed by the implant was larger than normal because of
tumor size and infiltration. The tumor dose exceeded 8500 cGy in
a large volume of the tongue.

39. Late effects
Muscle wasting and fibrosis
After completion of therapy the tongue mass was reduced
and tongue mobility and control impaired. Speech articulation
was dramatically affected and salivary control compromised.

40. Late Effects – Oral Mucous Membranes
This patient received 6800 cGy external beam therapy (CRT) for
a squamous cell carcinoma of the anterior floor of the mouth.
Note the scarring at the tumor site (arrow). However, there are
no signs of radiation effects beyond the tumor site.
This patient would be a good candidate for complete dentures. She is
compliant and the scarring and telangiectasia is confined to the tumor site.
However, overextension of the lingual flange in this region could result in a
mucosal perforation and lead to an osteoradionecrosis.

41. Late Effects – Oral Mucous Membranes
Patient received 6800 cGy for a squamous cell carcinoma of
the anterior floor of the mouth. Note the telangiectasias within
the zone of keratinized attached mucosa (ovals)
This patient would be a poor candidate for
a lower complete denture because the
bearing surface mucosa is thin and
atrophic and could be easily perforated by
a complete denture.

42. Late Effects – Oral Mucous Membranes
Patient received 6800 cGy for a squamous cell carcinoma of
the anterior floor of the mouth. Note the telangiectasias within
the zone of keratinized attached mucosa (ovals)
However, a maxillary complete denture would predispose to little risk.
These patients learn to masticate by mashing the bolus against the rugae
pattern, incorporated within the denture, with the tongue.

43. Soft Tissue Necrosis
A mucosal ulcer in irradiated tissue that has
no residual tumor
Clinical signs: The first priority is to rule out
a) Extremely painful recurrent tumor.
b) No inflammatory halo Diagnostic methods used:
c) No induration Cytology, biopsy and
clinical observation

44. Late Effects – Oral Mucous Membranes
" Soft Tissue Necrosis – Patient received 5500 cGy via external
beam and another 2500 cGy with a radium implant for a
squamous cell carcinoma of the lateral border of the tongue.
" Nine months after therapy he developed this ulceration at the
site of the tumor.
" Cytology and biopsy were negative and a diagnosis of radiation
soft tissue necrosis was assumed.
" The lesion epithelialized 4 months later

45. Acute Effects – Skin Reactions
In most patients skin reactions are limited to
erythema and tanning of the skin.
Individuals with light complexions are likely to
have the most severe skin reactions.

46. Acute Effects – Skin
Some patients develop dry
and moist desquamation of
the skin.

47. Late Effects - Skin
Scarring and telangiectasia
This patient received 5600 cGy for a squamous carcinoma
of the right cheek. After therapy he developed scarring and
telangiectasia of the cheek skin.

48. Late Effects - Skin
Alopecia, and hyper-pigmentation
Note the hair loss within the radiation field. This finding can be
very useful in identifying the fields of radiation when examining
a male post radiation (if CRT was used) particularly when the
radiation records are not available. Note the hyperpigmentation
(oval).

49. Late effects - Edema
v Secondary to obliteration of small lymphatic channels
and worsened by scarring and fibrosis (Engerset,
1964; Sherman and O’Brien, 1967).
v Clinically significant when it effects the tongue and
buccal mucosa
v Generally most prominent in the submental and
submandibular areas
v Radical neck dissection potentiates the effects and
increases the edema

50. Edema
Both patients present with edema of oral cavity structures, one
involving the tongue, the other the buccal mucosa. These two
patients are susceptible to tongue and cheek biting.
Prevention: Accomplished by use of a prosthetic stent designed to displace
the buccal mucosa or tongue away from the interocclusal surfaces
In edentulous patients the enlargement of the tongue has negative effects on
the floor of the mouth contour and adversely affects the lingual extension and
the patients ability to tolerate and control the lower denture.

51. Radiation and Trismus
v Secondary to fibrosis of the muscles of
mastication and generally not noticed
until 3-6 months after radiation
(Goldstein et al, 1999)
v The higher the dose the greater the
trismus (Goldstein et al, 1999).
v Occurrence is 10-45% (Kent et al,
2008).
v Mouth opening following radiation is
reduced by 18% (Dijkstra, 2004)
v The rate and severity is much higher
in patients treated with chemoRT
v Occurs more often when radiation is
combined with a surgical procedure
(i.e. radical maxillectomy) that effects
the TMJ and the muscles of
mastication.
v Risk and severity increases with time
particularly in patients treated with
chemoRT
v IMRT may decrease the risk (Hsiung et
al, 2008)

52. Radiation and Trismus
v Dramatically worsened by
concomitant chemotherapy
v Maximum opening may be
reduced to 5-15 mm
v Treatment consists of exercise
and use of dynamic bite
openers (Dijkstra et al, 2004).
v Progressively worsens with
time.
v Compromises the use of
complete dentures, obturator
prostheses.
*In patients with combined radiation and surgery, early initiation of an exercise
program before the fibrosis sets in provides the best results.

53. Radiation and Trismus
v This represents maximum opening for this
patient
v 13 years ago patient was treated with chemoRT
for a nasopharyngeal carcinoma

54. Radiation Trismus -Treatment
v Dynamic bite openers*# are the most effective form of
treatment (Dijkstra, 2004)
v Patient is instructed to stretch with the device for 30 minute
sessions three times per day.
v Requires a high level of patient cooperation because of the
discomfort associated with the required manipulation
v Tongue blades, taped together and used as a lever have
been less effective in increasing mouth opening.
*Therabite Corp., West Chester, PA
#Dynasplint Systems Inc., Severna Park, MD

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74. The End
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