1) Radiotherapy for head and neck cancer can cause both acute and late side effects in the treated tissues. Acute effects occur during or shortly after treatment while late effects present months to years later. 2) Common late side effects include xerostomia, dysphagia, skin changes like fibrosis and pigmentation changes, osteoradionecrosis of the jawbones, and endocrine dysfunction. 3) Intensity-modulated radiotherapy (IMRT) has allowed for better sparing of salivary glands and skin to reduce xerostomia and skin toxicity, but late effects still remain a challenge.

1. Side Effects of Radiotherapy To
the Head and Neck
DR HARIHAR

3. Acute vs. Late Effects
• • Acute (early) RT toxicity: – during or within
a few weeks after completion of treatment –
tissues with high cell turnover rate (mucosal
membranes, skin) – usually transient –
tissues with high α/β ratio – dose per fraction
not very

4. • Late RT toxicity: – months to years after
therapy – tissues with slow cell turnover rate
(low α/β ratio) – usually persistent and
progressive – fraction size matters

5. • Late Oropahryngeal Side Effects:
• Persistent Xerostomia
• Burning and Pain
• Mucositis
• Dysphagia
• Osteoradionecrosis

6. Consequential Late Effects
• • Severe early toxicity may be causally related
to subsequent late effects
• Both phases are manifestations of an
ongoing sequence of events initiated
immediately after injury
• Autocrine, paracrine and endocrine
messages resulting in dysregulation of the
tissue environment.

7. Grading Systems
• • The US NCI Common Terminology Criteria
for Adverse Events
• SOMA scale (Subjective, Objective,
Management, Analytic procedures)

8. Common Terminology Criteria for
Adverse Events

15. Mucositis
• • Dose-limiting toxicity of H&N RT
• Severe pain, dysphagia, weight loss
• Psychological distress, isolation, depression
• The most common cause of treatment
interruptions à possible negative impact on
treatment efficacy.

16. • Concurrent CRT is associated with increased
rates and more severe grades of mucositis
compared with radiotherapy alone
• The mucositis also occurs earlier during
treatment and lasts longer.

17. • 2/3 of patients have severe mucositis during
concurrent CRT
• 1/3 of patients in earlier trials were unable
to complete their planned treatment d/t
toxicity
Mucositis Usually begins ~2 weeks after
starting RT • Symptoms continue for 4-5
weeks after completion of therapy.

18. WHO s Oral Toxicity Scale
Oral Toxicity Scale Severe Mucositis
Grade 1 soreness with Erythema,
Grade 2 Mucositis extensive to the extent
ulcers.
Grade 3 patient cannot swallow solid food.
Grade 4 alimentation not possible.

23. • Wide variation in the methods of capturing,
grading and reporting (NCI- CTC, WHO criteria,
RTOG scale)
• The reported rates of mucositis vary
considerably among studies (25% to higher
than 80%)
• Physician-reported vs. patient-reported
symptoms.

24. Risk factors
• • Patient-related: –
Poor nutritional status – Poor dental
condition, poorly fitting dentures or oral
appliances
• Pre-treatment dental evaluation and
treatment is beneficial in reducing severity of
mucositis and ORN – Habits (Alcohol,
smoking, tobacco chewing).
Reduced/impaired salivary function Previous
cancer treatment.

25. • Treatment related: –
Concurrent chemotherapy, agent (5-FU, MTX)
and dose – Radiation dose, fractionation,
treatment site – More sensitive: lips,
pharyngeal wall, soft palate, tonsillar pillars,
buccal mucosa, lateral tongue, floor of mouth.

26. The 5-stage Model of Mucositis
Blijlevens N , Sonis S Ann Oncol
2006;18:817-826 © 2006 European
Society for Medical Oncology2012

29. Prevention and Treatment
• • No evidence-based guidelines!!!
• Self-care regimens for oral hygiene
• Avoidance of : – Chemical irritants
(tobacco, alcohol, spicy food, citrus fruits and
juices) – Physical irritants (extremes of hot
and cold foods, hard or coarse foods)
• Dietary changes as needed (pureed or liquid
diet).

30. • Pain medications
• Antibacterial or antifungal treatment as
needed – Candida Albicans is the most
common infection in pts receiving H&N RT.

31. Salivary Hypofunction Xerostomia•
• Proportional to the surface of salivary glands
receiving > 3000- 3500 Gy
• Effect is not reversible
• Low salivary output, viscous, sticky saliva.

32. • Dryness typically not relieved by sipping water
• Impaired speech
• Burning
• Pain
• Difficulty in chewing and swallowing.

33. • Taste disturbances aggravated by lack of
normal salivary function
• Chapped lips
• Major effect on nutrition, social function,
QOL.

34. • In the long term major effects on dental
health.
• Normal protective effects of saliva are not
available
• Caries, periodontal inflammation
• Lifelong increased risk for ORN!!

35. IMRT
• • Reduced dose to the noninvolved oral cavity
• Reduced and limited extent of acute
mucositis
• Sparing of minor salivary glands may further
improve xerostomia.

36. RT Skin Effects
• • RT-induced damage to the basal layer of the
epidermis; cells shed more rapidly
• Inflammatory response edema and
erythema
• Melanin rises to the surface characteristic
hyperpigmentation of irradiated skin.

37. • Begins 2-3 weeks after starting RT, continues
for 3-4 weeks after completion of therapy
• The effect is cumulative
• Mild erythema hyperpigmentation, dry
desquamation (dryness, pruritus) moist
desquamation.

38. Risk Factors
• • Patient-related: – Poor nutritional status –
Fair complexion –
Diabetes –
Connective tissue disease –
Burned skin, skin donor site etc.

39. • Treatment-related: –
Large field, electron-beam therapy, tangential
fields –
Post-op RT – Concurrent chemotherapy –
Thin epidermis (face, neck) – Bony
prominences – Susceptible sites: skin folds,
lips, ear lobes, incision lines or wounds,
peristomal skin.

40. Treatment
• • No evidence-based guidelines – General
skin care (cleaning, moisturizing) –
Avoidance of sun exposure –
Steroid cream +/- antibacterial ointments –
Silvadene ointment – Pain killers

41. Late Skin Effects
• • Thinning
• Telangiectasia
• Hair loss in the treated area
• Loss of sweat and sebaceous glandular
function
• Hyper/hypopigmentation.

42. H&N RT: Late Effects
• Xerostomia
• Swallowing dysfunction
• Vocal dysfunction
• Laryngeal edema necrosis
• Osteoradionecrosis (ORN)
• Hearing impairment
• Visual complications.

43. Other Oral-Oropharyngeal Side-Effects
• Trismus: Limitations in mouth opening and
jaw movements caused by fibrosis of
irradiated muscles –
Pain – Impaired chewing – Impaired oral
hygiene procedures – Problems in dental
treatment
• More severe in patients who also have
surgery involving mandible.

44. Taste alterations
• • Loss of taste, loss of appetite – Transient
but may become persistent – Major effect on
choice of food, malnutrition, weight loss .

45. Dysphagia
• Field length greater than 82 mm at second
phase of Rx
• Concurrent chemotherapy
• Site
• Increasing age
• All increase risk for long term dysphagia.

46. Esophageal Pathology in Patients After
Treatment for Head and Neck Cancer
• Peptic esophagitis (63%) –
Stricture (23%) –
Candidiasis (9%) –
Barrett metaplasia (8%) –
Gastritis (4%) –
Carcinoma (4%) –
Only 13% had a normal esophagoscopy
(Farwell et al. Otolaryng Head Neck Surg 2010
Sep;143(3):375-8).

47. • Esophageal changes after treatment for HNCA
are likely multifactorial and related to: –
Changes in bacterial flora – Mucosal injury
from chemoradiation therapy – Fibrosis
Xerostomia and its resultant change in pH –

48. • Use of a PPI was not associated with the
endoscopic diagnosis of esophagitis in this
cohort (P > 0.05)It is unclear if the severity of
the esophagitis would have been worse had
they not been on the PPI.
( Farwell et al. Otolaryng Head Neck Surg 2010
Sep;143(3):375-8).

49. • Minimizing dose to the pharyngeal
constrictors and larynx to < 60 Gy when
possible
• Other causes – fibrosis, vascular and nerve
damage.

50. Osteoradionecrosis •
• Bone within the radiation field becomes
devitalized and exposed through the overlying
skin or mucosa, persisting as a non- healing
wound for three months or more

51. etiopathology
• Endarteritis
• Tissue hypoxia
• Hypocellularity
• Hypo-vascularity
• Tissue breakdown and chronic non- healing
wounds.

52. • Suppression of osteoclast related bone
turnover is the initial event in development of
ORN

53. Fibro-Atrophic Theory
• fibroblast populations undergo total cellular
depletion but also show a reduced ability to
produce and secrete collagen; free radical
formation, endothelial dysfunction,
inflammation, microvascular thrombosis,
fibrosis and remodeling, and finally bone and
tissue necrosis. (Delanian S, Lefaix JL.
Radiother Oncol 2004;73:119–31)

54. Epidemiology of ORN
• Most frequently noted in the first few years
after completion of treatment (70–94%)
• Early onset ORN (<2 ) related to radiation
doses > 70 Gy or surgical trauma
• Late onset ORN, is thought to arise from
trauma in a chronically hypoxic tissue
environment.

55. Mandibular Osteoradionecrosis in
Squamous Cell Carcinoma of the Oral
Cavity and Oropharynx: Incidence and
Risk Factors
• The incidence of mandibular ORN was 40% at
5years.
Mandibular surgery before irradiation is the
only independent risk factor.

56. Additional Risk Factors
• Drugs:
• Abuse of alcohol and tobacco is clearly
identified as risk factor for ORN.
• 89% of patients with ORN generally
continue smoking.

57. • COMPLETE RESTORATION OF REFRACTORY
MANDIBULAR OSTEORADIONECROSIS BY
PROLONGED TREATMENT WITH A
PENTOXIFYLLINE-TOCOPHEROL-CLODRONATE
COMBINATION (PENTOCLO): A PHASE II TRIAL

58. Conclusion
• Long-term PENTOCLO treatment is effective,
safe, and curative for refractory ORN and
induces mucosal and bone healing with
significant symptom improvement

59. ORN After IMRT
• RTOG-0022 study reported an incidence of 6%
ORN in oropharynx cancer patients treated at
fraction size of 2.2gy per fr (–66 Gy )without
chemotherapy.

60. HBO in Treatment of ORN of Jaws???
• A systematic review in 2008 did not show
value of hyperbaric oxygen therapy for
osteoradionecrosis

61. Radiotherapy Effects on Larynx
• Dysphonia and laryngeal edema are potential
long-term complications of radiotherapy for
HNCa •

62. • The impact of dysphonia can result in severe
distress and potential financial loss from sick
leave
• Irradiation of the neck results in dryness of
the submucosal laryngeal glands, abnormal
vocal cord vibration, and in severe case
laryngeal edema with resulting chronic
dysphonia.
( G. Sanguineti, et al. Int J Radiat Oncol Biol
Phys,)

63. • Laryngeal edema severity correlates with the
radiation dose delivered to the larynx
• Significant when mean dose > 43.5 Gy
• For laryngeal and hypopharyngeal cancers,
high doses to the larynx are unavoidable
frequently resulting in long-term vocal cord
edema.

64. • (32%) had clinically significant aspiration and
(37%) developed a stricture.
• the volume of the larynx receiving >or=50
Gy and volume of the inferior constrictor
receiving >or=50 Gy were significantly
associated with both aspiration and stricture.

65. Complications After Radiation
Treatment Base of Skull
• Endocrinopathy
• Cranial neuropathy
• Visual deficits
• The exposure of the optic apparatus,
pituitary stalk, and brainstem must be
considered during planning to minimize
complications.

66. • If the optic apparatus is included in the 80%
isodose line, it might be best to fractionate
therapy
• Exposure of the pituitary stalk should be
kept to <30 Gy to minimize endocrine
dysfunction.
• Brainstem exposure should be limited to
<60 Gy in fractions.

73. Oral Complications
• Xerostomia is an almost universal
complication from treatment
• with conventional RT and may lead to dental
caries.
Jen et al, showed that the salivary flow
dropped by half with a dose of 7.2 Gy, reached
the nadir after 36 Gy, and then further
dropped after completion of RT without
recovery during the following 2 years.

74. • However, Lee at al reported marked recovery
of salivary function in patients treated with
parotid-sparing IMRT (mean parotid dose, 34
Gy); the rate of grade 2 xerostomia decreased
from 64% at 3 months to 2.4% at 2 years
Randomized trials comparing 2D RT and IMRT
in patients with T1-2 tumors confirmed IMRT’s
advantage in this regard.

75. • Nevertheless, it is important to rule out tumor
invasion of the parotid gland prior to parotid-
sparing IMRT, as recurrences have been
reported.

76. • Cannon and Lee concluded that PET alone
may be insufficient for detection of
intraparotid lymph node involvement in
patients with multilevel nodal disease,
including disease in level II nodes. Even with
negative PET findings, these patients may
require additional evaluation of any benign-
appearing parotid nodules before parotid-
sparing IMRT by fine-needle aspiration or CT-
guided biopsy.

77. • Dental sequelae frequently accompany
xerostomia.
In a series of 1,758 patients, 2.7% developed
osteoradionecrosis at the maxilla and 1.7% at
the mandible.

78. • Tong et al reported a29% complication rate in
patients who had post-RT extraction of
posterior maxillary teeth, with 10.5%
developing osteonecrosis.
• Prophylactic fluoride treatment should be
employed to prevent dental decay, and
decayed teeth should be extracted prior to RT
to reduce this risk.

79. Aural Toxicity
• Hearing loss has always been a common radiation
sequele, and the increasing use of cisplatin-based
concurrent CRT has resulted in deafness rates as
high as 42%. Sensorineural hearing loss (SNHL),
particularly in the highfrequency range, was
found in at least 30% of patients assessed with
audiograms following RT, with higher rates in
patients treated by concurrent CRT. The primary
determinant of high-frequency SNHL is mean
cochlea dose, which should be kept below 48 Gy
to minimize damage.

80. • Due to the location of the primary tumor in
the nasopharynx, pharyngotympanic tube
(Eustachian tube) damage resulting in otitis
media is difficult to avoid. However, lowering
the dose to the external auditory canal and
mastoid air cells can reduce the incidence and
severity of acute external otitis and chronic
serous otitis media, respectively.

81. Endocrine Dysfunction
• The most common endocrine sequelae are
amenorrhea and/or galactorrhea from
hyperprolactinemia in female patients, followed by
hypothyroidism and hypoadrenalism.
Lee et al. observed symptomatic hypothalamic–
pituitary dysfunction in 5% of patients, with a median
latency of 5 years while a longitudinal study by Lam et
al. with detailed endocrine assessment found a 5-year
incidence of 62%, with dysfunction detected as early as
1 year following RT. The deficiency of releasing or
inhibitory factors indicated that the hypothalamus is
the primary location of damage.

82. • As many of these dysfunctions may be corrected
pharmacologically, routine evaluation of
hypothalamic, pituitary, and thyroid function
should be considered in the follow-up
examination of long-term survivors.
• Shielding may help lessen endocrine dysfunction
when using 2D technique.341 The need for
maximum conformity to protect normal tissues
during radiotherapy is paramount.

83. Temporal Lobe NecrosIS
• Temporal lobe necrosis (TLN) is perhaps the
most troublesome complication. Studies on
NPC patients treated with conventional 2D RT
found that TLN accounted for up to 65% of all
irradiation-induced deaths; large fractions (>2
Gy) and overacceleration of treatment
schedule greatly increased risk, with incidence
as high as 33%.

84. • Diagnosis of TLN was often difficult and thus
delayed. In Lee et al.’s examination of 102
patients with late TLN following conventional 2D
RT,only 31% presented with classic symptoms of
TLN (hallucinations, absence attacks, déjà vu),
while 14% had headaches, confusion,
convulsions, or hemiparesis. Thirty-nine percent
had vague symptoms of dizziness, poor memory,
or sudden changes in behavior, while 16% were
asymptomatic.

85. • TLN remains a serious concern in patients
treated with IMRT, with incidence of 3% to 4%
being reported for schedules of 70 Gy at 2.12
Gy/fraction, 66 to 74 Gy at 2 Gy/fraction, and
76 Gy at 2.17 Gy/fraction.Series using larger
fractions (70.2 Gy at 2.34 Gy/fraction and 68
Gy at 2.27 Gy/fraction) had incidence rates as
high as 12% to 14%.

86. • Bakst et al., in a prospective trial of
hypofractionated dose-painting IMRT using
2.34-Gy fractions to deliver a total dose of
70.2 Gy, had favorable disease control and
survival outcomes; however, 12% of treated
patients developed temporal lobe necrosis,
and the conclusion was that large fractional
doses should be avoided to prevent in-field
brain radiation necrosis.

87. Cranial Neuropathy
• Cranial nerves IX through XII, particularly XII, are the
most frequently
• impaired by radiation.
This is related to marked radiation fibrosis, especially in
patients who receive an additional boost dose to
parapharyngeal space. Common symptoms include
slurring of speech, twitching of neck muscles, and/or
dysphagia. In a study of 31 NPC patients with post-RT
dysphagia, Wu et al.322 found that 77% aspirated after
the act of swallowing, raising concerns of fatal
aspiration pneumonia.

88. • Cranial nerve VI is also frequently affected,
particularly in patients with TLN, while
isolated palsy of branches of cranial nerve V is
less common.

89. • Optic neuropathy is rare with careful attention
to the RT technique and should be considered
when treating lesions with base-of-skull
involvement. The possibility of intracranial
recurrence may confound the diagnosis of
radiation injury, and exclusion of recurrence is
necessary.

90. Carotid Artery Injury
• Carotid stenosis is a potentially fatal
complication reported in
• patients who undergo irradiation of the head
and neck region.
• Interval from radiotherapy was a significant
independent predictor for severe carotid
stenosis.

91. • Some have advocated for routine duplex
ultrasound screening for high-risk patients
• (age >60 years, smoking, hypertension,
hypercholesterolemia cerebrovascular
symptoms).
Severe cases may require carotid
endarterectomy or endoplasty.

92. • Massive bleeding from ruptured
pseudoaneurysms at the petrous portion of
the internal carotid has been reported
following IMRT with dose escalation.178,336
Urgent diagnosis and intervention with
endovascular occlusion or stenting may be
needed to prevent fatal consequences.

93. • Other concerns include severe telangiectasia
and hypervascularization in the internal
maxillary artery territory, for which emergency
embolization may be considered.

94. Second Malignancies
• Radiation-induced malignancy is rare, with an
incidence of 0.04% and latency period of >10
years. The most common histologic types are
maxillary osteosarcomaand soft tissue
sarcoma.

95. • Surgery presents the only chance of cure, but
the prognosis is often poor. While second
primary head and neck cancer is relatively
uncommon for NPC patients, Teo et
al,reported an excessive incidence rate of
tongue cancer at 0.13% per patient-year. The
possibility of radiation carcinogenesis cannot
be excluded.