1. The International Federation
of Head and Neck Oncologic Societies
Current Concepts in Head and Neck Surgery and Oncology 2012
Complications from Radiation
Therapy
Alexander Rapidis

2. Radiation Therapy
General Statements
• Radiation alone or with other treatment
modalities is used in a significant number of
patients with advanced stage oral cancer
• A therapeutic dose of 50-70 Gy is externally
delivered to the tumor
• Usually, increments of 200 cGy/day is
delivered until the accumulated dose is
2012
achieved

3. Mucositis
Acute (Early) Acute
Skin Reactions Infection
Chronic
Xerostomia
Oral Complications
of radiotherapy
Radiation caries
Chronic (Late) Trismus
Radiation induced
malignancies
Osteoradionecrosis
2012

4. Acute
Mucositis
2012

5. Mucositis
Symptoms
• Intense pain
• Food and fluid intake decreases
• Speech and swallowing becomes difficult
• Its intensity may require ceasing therapy
2012

6. WHO Oral Mucositis Scale
Severe
Oral Mucositis
Grade
0 1 2 3 4
None Soreness Erythema, Ulcers, Mucositis
+/– ulcers extensive to the extent
erythema erythema that
Patients alimentation is
No can Patients not possible
ulceration swallow cannot
solid diet swallow solid
diet
2012

7. Mucositis
Clinical Characteristics
Grade I Painless ulcers, erythema, or mild
soreness
in the absence of ulcers
2012

8. Mucositis
Clinical Characteristics
Grade II Painful erythema, edema, or ulcers but eating
or swallowing possible
2012

9. Mucositis
Clinical Characteristics
Grade III Pseudomembranous surface
Ulcers, extensive erythema. Patients cannot swallow
solid diet
2012

10. Mucositis
Clinical Characteristics
Grade IV Ulcerations
Oral mucositis to the extent that alimentation is not
possible
2012

11. Mucositis
Management
• Mucosal coating agents
• Cleansing devices
• Chlorhexidine
• Recombinant keratinocyte growth factor
• GMCSF (Combined Therapy)
• Thalidomide?
2012
• Low-level laser therapy?

12. Acute Skin Reactions
2012

13. 2012

14. 2012

15. 2012

16. Late Xerostomia
2012

17. Xerostomia
Pathogenesis
– Irreversible acinar cell damage
Clinical Characteristics
– 50% decreased salivation after 1 week of
radiation
– 75% decrease after 6 weeks
– 95% decrease years after
– Thick ropey saliva
2012 – Candida albicans infection
– Dysphagia / Odynophagia

18. Xerostomia
Symptoms
• Difficulty in eating, speaking, & swallowing
• Taste disorders
2012

19. Pre-treatment Strategies
Current
IMRT / Conformal beam design
Radioprotective agents
• Amifostine
• Antioxidants
Salivary stimulation
• Pilocarpine; cevimeline;
gustatory;
• other agents
2012

20. Tumor
Dose
Tissue
Conventional Intensity
Radiotherapy Modulated
Radiotherapy
2012

21. Sparing the parotid glands with IMRT
significantly reduces the incidence of
xerostomia and leads to recovery of
saliva secretion and improvements in
associated quality of life, and thus
strongly supports a role for IMRT in
squamous-cell carcinoma of the head
and neck.
2012
www.thelancet.com/oncology Published online January 13, 2011

22. Xerostomia
Treatment
• Lubricants
• Gustatory stimulation
• Drug intervention
• Submandibular gland
relocation
2012
• Daily living “tricks” or
maneuvers

23. Late Radiation Caries
2012

24. Radiation Caries
Pathogenesis
• Shift to cariogenic microflora and
xerostomic environment
Clinical Characteristics
• Cervical, cusp, & incisal decay
• Coronal fractures
2012

25. Late Trismus
2012

26. Trismus
• More common with high posterior fields of
radiation
– as muscles of mastication are in field
(10%)
• Retention of coronoid process
• Made worse by concomitant chemotherapy
2012

27. Trismus
Pathogenesis
• Direct effects of radiation on muscles and/or TMJ
Clinical Characteristics
• Limited range of motion
Management
• Prevent with stretching exercises
• Prophylactic or therapeutic pentoxifylline, a-
2012
tocopherol

28. Late Radiation
Induced Malignancies
2012

29. Late Complications Following RT
No Event occurs
event above threshold
dose, severity ↑
with dose
Event can occur at any dose
level
Probability, not severity, ↑ with
dose
2012
Increasing RT Dose

30. Late Complications Following RT
Xerostomia
Soft tissue
fibrosis
Osteoradionecros
is
Radiation associated
tumors
2012
Increasing RT Dose

31. 2012

32. Late
Osteoradionecrosis
2012

33. Background
• Devastating complication of radiation
therapy that can be more difficult to
treat than original tumor
• Clinical definition:
Devitalized, irradiated bone that is
exposed through overlying mucosa or
2012 skin persisting for > 6 months

34. Osteoradionecrosis is the clinical condition in which irradiated bone
becomes devitalized and exposed through the overlying skin or
mucosa persisting without healing for 3 months.
2012
Marx RA, J Oral Maxillofac Surg 1983

35. Osteoradionecrosis is perhaps the most dreaded late
complication of radiotherapy affecting mandibular bone more
frequently than any other bone in the head and neck.
2012

36. The Etiology of
Osteoradionecrosis
2012

37. Pathophysiology of Osteoradionecrosis.
Direct radiation effects on normal tissue may be
lethal or sublethal
Lethal damage is caused by
ionization within the desoxyribonucleinic acid
(DNA) preventing cell replication and resulting in
tissue death
2012
Sublethal damage may cause cell mutation
leading to further neoplasia

38. The irradiated mandible, periosteum, and overlying
soft tissue undergo hyperemia, inflammation,
and endarteritis.
These conditions ultimately lead to thrombosis,
cellular death, progressive hypovascularity, and
fibrosis.
2012

39. 3 “H” Hypothesis &
Osteoradionecrosis
Hypovascularity
Hypoxia
Hypocellularity
Tissue injury (usually)
Tissue breakdown / non-healing wound
2012

40. The incidence of osteoradionecrosis varies considerably between various
studies and is reported to be between 1-40% of patients receiving
radiotherapy in the head and neck area.
Mendenhall WM J Clin Oncol 2004
2012
Reuther et al, Int J Oral Maxillofac Surg 2003

41. 2012
S. Vudiniabola, C. Pirone, J. Williamson, A. N. Goss: Hyperbaric oxygen in the therapeutic
management of osteoradionecrosis of the facial bones. Int. J. Oral Maxillofae. Surg. 2000; 29:
435-438.

42. 2012
M.J. Wahl, Int J Radiation Oncology Biol Phys, 64:3, 661–9, 2006

43. • Osteoradionecrosis presents as a broad
spectrum of disease severity
• It is rare at radiation therapy doses of less 60 Gy
• It is more common when brachytherapy is used
• The mandible must be in the treatment volume area
• Dental extractions, surgery or trauma usually
proceed its onset
• Secondary infection may be present
2012

44. Factors Affecting the Occurrence of Osteoradionecrosis.
1. Field of irradiation
2012
Thorn JJ et al, J Oral Maxillofac Surg 2000

45. 2. The dose of irradiation
Total doses above 64 Gy resulted in 95% of cases with
osteoradionecrosis of the mandible in a cohort of 80 patients
Thorn JJ et al, J Oral
Maxillofac Surg 2000
Curi MM and Lauria L, J Oral
Maxillofac Surg 1997
2012

46. 3. Time after radiation treatment
Most of the reported cases of osteoradionecrosis of the mandible
occur between 2-5 years after radiation treatment
Thorn JJ et al; J Oral Maxillofac Surg 2000
2012
Fujita M et al, Int J Rad Oncol Biol Phys 1996

47. 4. Variation in treatment fractionations
Conventional fractionation and total dose 67,0-72,0 Gy: ORN 20,1%
Hyperfractionated irradiation and total dose 72,0-78,8 Gy: ORN 6,6%
2012
Studer G et al, Strahlenther Onkol 2004

48. 5. Type of radiation treatment
Brachytherapy is reported to cause the highest rate of osteoradionecrosis of
the mandible. The use of spacers may reduce its occurrence
2012
Miura M et al, Int J Radiation Oncology Biol Phys 1998

49. Intensity Modulated Radiation Therapy (IMRT)
Conformal radiotherapy reduces the dosage to the mandibular bone when
the mandible is not the target of treatment
2012
Claus F et al, Oral Oncology 2002

50. The Dental Extraction After Radiation
Therapy
2012

51. Extractions & Osteonecrosis
Traditional Concepts
• Twice the risk of ORN is seen when selected
teeth are extracted following radiation
therapy
• Pre-radiation extractions associated with a
lower risk of ORN
• Risk of ORN persists for years and reduced
2012
healing capacity may be considered
permanent

52. Tooth extraction and dental disease in irradiated regions have long been
recognized as the major risk factors in the development of
osteoradionecrosis.
Thorn JJ et al, J Oral Maxillofac Surg 2000
2012
Støre G et al, Clin Otolaryngol 2002

53. Nearly 85% of 1,194 irradiated patients followed in the
MSKCC Dental Service from 1998 through 2001 did not
require dental extractions to prevent ORN. Our
retrospective data review indicated that only 11 of 1,194
patients (0.92%) developed ORN, including 4 patients
2012 (2.14%) who had extractions at MSKCC, a much lower
rate than that typically reported in the literature.

54. In conclusion, the present study showed a low
prevalence of ORN related to exodontia: only 2
ORN (0.5%) cases associated with 1.647
exodontia performed before radiotherapy and 1
ORN case (1.7%) in 290 exodontia after
2012
irradiation.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105:e1-e6

55. Incidence of ORN in the mandible
Angle
12%
Body
Mental 86%
2%
2012

56. 2012

57. Classification of Osteoradionecrosis of the
Mandible
2012

58. There are several classifications for mandibular osteoradionecrosis
and they all stage the disease according to the severity of signs and
symptoms in either Stages, Grades or Scores
2012

59. 2012
RTOG: Radiation Therapy Oncology Group
Jereczek-Fossa BA and Orecchia R, Cancer Treatment Reviews 2002

60. 2012
Epstein J et al, Oral Surg 1997

61. Stage I
Superficial
Ulceration
2012 Exposed cortical
bone
Schwartz HC and Kagan AR, Am J Clin Oncol 2002

62. Stage II
Exposed medullary
bone
+ soft tissue changes
2012
Schwartz HC and Kagan AR, Am J Clin Oncol 2002

63. Stage III
Sinus/Fistula
Pathologic Fracture
2012
Schwartz HC and Kagan AR, Am J Clin Oncol 2002

64. Management of Early and
Advanced
Osteoradionecrosis
2012

65. The Role of Hyperbaric Oxygen
2012

66. The Role of Hyperbaric Oxygen
HBO treatment involves the delivery of 100% oxygen at high
pressure in special chambers. The pressure of the oxygen inhaled by
the patient is usually 2.4 times more than the atmospheric pressure
and can be as high as 3 times more.
2012

67. Most of the literature indicates that HBO has no impact
on tumor growth - be it stimulatory or inhibitory.
2012

68. However, the general consensus is that HBO
does not offer any significant clinical benefits or
improvement in survival
2012

69. Advocates of HBO therapy support the view that HBO represents the only medical
treatment for osteoradionecrosis. HBO can revert the delayed radiation changes in
tissues by generating steep oxygen gradients between the normal and the
irradiated tissues causing oxygen to diffuse into the affected areas.
2012

70. The Role of Hyperbaric Oxygen
HBO has been used as an adjunctive conservative measure along
with antibiotics and irrigation since the 1960s.
Using Marx’s theory that osteoradionecrosis is a result of hypoxia,
hypocellularity and hypovascularity, HBO seems likely to increase
oxygen supply in hypoxic tissues, stimulating fibroblast proliferation
and angiogenesis.
2012

71. The role of HBO in the
treatment of
osteoradionecrosis.
The Marx protocol
(1982)
2012
Gal TJ et al, Arch Otolaryngol Head Neck Surg 2003

72. The use of HBO in the treatment of osteoradionecrosis despite its widespread
use had been largely theoretical or anecdotal because of the paucity of
controlled trials and the lack of unified assessment of symptom
improvement.
2012
Epstein J et al, Oral Surg 1997

73. The role of HBO in
the treatment of
osteoradionecrosis.
The study by
Annane et al
(2004)
The first randomized,
placebo-controlled,
double-blind study
assessing the
efficacy and safety of
HBO for the
treatment of overt
mandibular
osteoradionecrosis
and included 68
patients.
2012
Annane D et al, J Clin Oncol 2004

74. The trial was terminated prematurely because of the failure to demonstrate
any beneficial effect of HBO over placebo (19% vs. 33% respectively).
They also reported the progression of disease in recovery in the arm of HBO
patients and better recovery rates in the arm of the placebo treated patients.
2012
Annane D et al, J Clin Oncol 2004

75. The study by Annane resulted into strong criticism and
disbelief by several authors quoting that it violated an
ethical principle by exposing the control group to the
potentially serious risk of acute decompression illness; a
risk not present in the treatment group.
Others stated that a major error in Annane’s study was the
fact that the studied group of patients with an
osteoradionecrosis was not well defined.
There were though supporters of the Annane study
presenting evidence that the beneficial results of HBO
2012
treatment are equivocal and the method is time
consuming and expensive.

76. Although the cohort was small it seems that HBO
was of little benefit. HBO is demanding for patients
and has cost implications for the NHS; hence
further clinical outcome data are urgently required
with regard to its role in the management of ORN.
2012

77. HBO therefore remains ineffective as a stand-alone
therapy or even as a reliable adjuvant. Variability
among investigation techniques at various centers
makes it difficult to completely write off HBO as a
potential therapeutic adjuvant.
The debate is still going on.
2012

78. The use and efficacy of HBO prior to tooth extraction
has been debated in the literature.
Those who argue against the use of HBO prior to tooth
extraction state that:
the overall risk of developing ORN with pre-radiation
or postradiation extractions is quite low,
HBO therapy is expensive, and
it is time consuming
2012

79. The use of HBO therapy prior to implant placement has
also been debated. The use of HBO may decrease
morbidity and increase the success of dental implant
therapy. Recent studies have shown an increase in long-
term dental implant failure in patients who did not
receive HBO with implant placement.
2012

80. Management of Early and
Advanced
Osteoradionecrosis
2012

81. Established ORN does not regress
spontaneously.
It either stabilizes or gradually
worsens.
2012

82. 2012

83. 2012

84. 2012

85. One of the adverse factors implemented in the
development of ORN is the Radiation Induced
Fibrosis (RIF) and necrosis.
It has been shown that RIF greatly regressed after
antioxidant treatment with the combination of
pentoxifylline, tocopherol and clodronate.
2012
Delanian S et al Head Neck 2005

86. With this treatment applied to 18 patients with advanced ORN,
16 (89%) recovered after a median 6 months of treatment.
The results of this trial raise many questions primarily about the
precise mechanisms of action of the drugs used, which will remain
unanswered until further randomized clinical trials will be conducted.
2012
Delanian S et al Head Neck 2005

87. Selection of Treatment in ORN
Stage I
Superficial Ulceration
Exposed cortical bone
Conservative
management:
Debridement
Meticulous oral hygiene
Antibiotics
2012

88. Stage I: Perform 30 HBO dives (1 dive per day, Monday-Friday) to 2.4
atmospheres for 90 minutes.
Reassess the patient to evaluate decreased bone exposure, granulation
tissue that covers exposed bone, resorption of nonviable bone, and absence
of inflammation.
For patients who respond favorably, continue treatment to a total of 40
dives. For patients who are not responsive, advance to stage II.
2012

89. Selection of Treatment in ORN
Stage II
Exposed medullary bone
+ soft tissue changes
Conservative Surgical
management:
Sequestrectomy
in addition to other
conservative measures
HBO cannot revitalize dead
bone
2012

90. Stage II: Perform transoral sequestrectomy
with primary wound closure followed by
continued HBO to a total of 40 dives.
If wound dehiscence occurs, advance
patients to stage III.
Patients who present with orocutaneous
fistula, pathologic fracture, or resorption to
the inferior border of the mandible advance
2012 to stage III immediately after the initial 30
dives.

91. Selection of Treatment in ORN
Stage III
Sinus/Fistula
Pathologic Fracture
Extensive soft tissue
involvement
Extensive bony loss
2012

92. 2012

93. Stage III: Perform transcutaneous mandibular resection, wound
closure, and mandibular fixation with an external fixator or
2012 maxillomandibular fixation, followed by an additional 10
postoperative HBO dives.

94. The only successful treatment of advanced
(Stage III) mandibular osteoradionecrosis is the
surgical resection of diseased tissues and their
reconstruction with free tissue transfer
2012

95. Conservative measures, such as limited debridement
and HBO therapy, may be effective in preventing the
progression of ORN. However, they fail to eradicate
established ORN, which requires radical surgical
resection followed by functional reconstruction with
2012
well-vascularized tissue.

96. Patients who initially present with advanced disease
(stage II or III) are unlikely to respond to HBO and
conservative therapy. These patients require
extensive debridement leading to large composite
defects.
2012

97. 2012

98. 2012

99. 2012

100. Reconstructive options in the treatment of
severe (Stage III) mandibular osteoradionecrosis
1. The radial forearm osteocutaneous flap
2. The fibula osteocutaneous flap
3. The use of additional flaps
2012

101. 2012
Militsakh ON et al, Otolaryngol-Head and Neck Surg 2005

102. 2012

103. 2012

104. 2012

105. 2012

106. 2012

107. Reconstructive options in the treatment of
severe (Stage III) mandibular osteoradionecrosis
1. The radial forearm osteocutaneous flap
2. The fibula osteocutaneous flap
3. The use of additional flaps
2012

108. 2012
Shaha A et al, Head Neck 1997

109. 2012

110. 2012

111. 2012

112. 2012

113. 2012

114. Reconstructive options in the treatment of
severe (Stage III) mandibular osteoradionecrosis
1. The radial forearm osteocutaneous flap
2. The fibula osteocutaneous flap
3. The use of additional flaps
2012

115. • Iliac crest (DCIA)
• Scapula
• Latissimus dorsi
• Rectus Abdominis
• Lateral arm
• Lateral thigh
2012

116. The rate of post-operative complications during
the surgical treatment of mandibular
osteoradionecrosis is extremely high and when
they occur usually require additional surgery
.
2012
Ang E et al, Br J Plast Surg 2003
Gal TJ et al, Arch Otolaryngol Head Neck Surg 2003

117. 2012

118. 2012

119. 2012

120. Conclusion
• Early ORN can be managed conservatively
• Successful treatment of advanced ORN
depends on resection of all necrotic tissue
• Predictable and prompt primary healing of
surgical defect requires well-vascularized
tissue
• Single-stage composite microvascular
tissue transfer provides best opportunity to
2012
achieve successful outcome

121. The question whether HBO should be a
precedent treatment or should be
administered post-operatively or not at all is
unanswered.
2012

122. Conclusions
• Combined modality treatment for oral cancers is
associated with multiple early and late effects which
impact QOL
• Oral complications are common following radiation for
head and neck cancer
• Irradiation of parotid glands is the main cause of
xerostomia
• IMRT reduces the risk of xerostomia
• Pharmacological approaches such as amifostine may have
a similar effect
• The future challenge is to study interventions to reduce
2012 adverse effects in the oral tissues and improve QOL