1. The International Federation
of Head and Neck Oncologic Societies
Current Concepts in Head and Neck Surgery and Oncology 2012
Side Effects of Radiotherapy
To the Head and Neck
Dan Fliss

2. 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
2012
important

3. Acute vs. Late Effects
• 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
2012
(BED)

4. Late Oropahryngeal Side Effects:
• Persistent Xerostomia
• Burning and Pain
• Mucositis
• Dysphagia
• Osteoradionecrosis
• Rampant caries/ dental disease
2012
Head and Neck Cancer: Multimodality Management
By Jacques Bernier

5. 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
2012
the tissue environment

6. Consequential Late Effects
2012

7. Defining Late Toxicity - Difficulties
• Late effects are underscored and
underreported
• Selection of clinically relevant
outcomes
• Uniform grading of late effects
• Multi-modality therapy
2012 • Tumor and host factors may interact
with therapy

8. Grading Systems
• The US NCI Common Terminology
Criteria for Adverse Events
• SOMA scale (Subjective, Objective,
Management, Analytic procedures)
2012

9. Mucositis
2012

10. 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
2012
impact on treatment efficacy

11. Mucositis
• Concurrent CRT is associated with
increased rates and more severe
grades of mucositis compared with
radiotherapy alone
• The mucositis also occurs earlier
2012
during treatment and lasts longer

12. Mucositis
• ~2/3 of patients have severe
mucositis during concurrent
CRT
• ~1/3 of patients in earlier trials
were unable to complete their
2012
planned treatment d/t toxicity

13. Mucositis
• Usually begins ~2 weeks
after starting RT
• Symptoms continue for
4-5 weeks after
completion of therapy
2012

14. WHO s Oral Toxicity Scale
World Health Organization s Oral Toxicity
Scale
Severe Mucositis
Grade 1 Grade 2 Grade 3 Grade 4
Ulcers with
Erythema, Mucositis
extensive
to the extent
ulcers; erythema;
Soreness that
patient can patient
± erythema cannot
alimentation
swallow is not
solid food swallow
possible
food
2012

15. Mucositis
• 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
2012

16. Mucositis – 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)
2012
– Reduced/impaired salivary function
– Previous cancer treatment

17. Mucositis – Risk factors
• Treatment related:
– Concurrent chemotherapy, agent (5-FU,
MTX) and dose
– Radiation dose, fractionation, treatment
site
– More sensitive: lips, pharyngeal wall, soft
2012 palate, tonsillar pillars, buccal mucosa,
lateral tongue, floor of mouth

18. The 5-stage Model of Mucositis
Blijlevens N , Sonis S Ann Oncol
2006;18:817-826
© 2006 European Society for Medical
Oncology
2012

19. Mucositis – 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)
2012

20. Mucositis – Treatment
• Pain medications
• Antibacterial or antifungal treatment
as needed
– Candida Albicans is the most common
infection in pts receiving H&N RT à
2012

21. Salivary Hypofunction
Xerostomia
• Proportional to the surface of salivary
glands receiving > 3000- 3500 Gy
• Effect is not reversible
• Low salivary output, viscous, sticky
saliva
2012

22. Dose-Volume Data
Complication
probability
curves as a
function of the
mean parotid
dose
2012

23. Salivary Hypofunction
Xerostomia
• Dryness typically not relieved
by sipping water
• Impaired speech
• Burning
• Pain
2012
• Difficulty in chewing and swallowing

24. Salivary Hypofunction
Xerostomia
• Taste disturbances
aggravated by lack of
normal salivary function
• Chapped lips
• Major effect on nutrition,
social function, QOL
2012

25. Salivary Hypofunction
Xerostomia
• 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!!
2012

26. IMRT
• Reduced dose to the noninvolved
oral cavity
• Reduced and limited extent of acute
mucositis
• Sparing of minor salivary glands
2012 may further improve xerostomia

27. Xerostomia
• Common late toxicity with a huge impact on QoL
• Leads to multiple problems:
– Difficulty speaking
– Difficulty chewing and swallowing
– Halitosis
– Altered taste
– Complaint of burning mouth, lips, or tongue
– Dental problems, a propensity to oral infections
2012
– Sleep disturbances

28. Sparing of the parotid glands only
may not be sufficient!
2012

29. Limited Success in Relieving
Xerostomia
2012

30. RT Skin Effects
• RT-induced damage to the basal layer of
the epidermis; cells shed more rapidly
• Inflammatory response à edema and
erythema
• Melanin rises to the surface à
characteristic hyperpigmentation of
2012
irradiated skin

31. RT Skin Effects
• Begins 2-3 weeks after starting
RT, continues for 3-4 weeks after
completion of therapy
• The effect is cumulative
• Mild erythema
àhyperpigmentation à
dry desquamation (dryness,
2012
pruritus) à moist desquamation

32. 2012

33. RT Skin Effects – Risk Factors
• Patient-related:
– Poor nutritional status
– Fair complexion?
– Diabetes
– Connective tissue disease
– Burned skin, skin donor site etc.
2012

34. RT Skin Effects – Risk Factors
• 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
2012
lobes, incision lines or wounds,
peristomal skin

35. RT Skin Effects - Treatment
• No evidence-based guidelines
– General skin care (cleaning,
moisturizing)
– Avoidance of sun exposure
– Steroid cream +/- antibacterial
ointments
– Silvadene ointment
2012
– Pain killers

36. Late Skin Effects
• Thinning
• Telangiectasia
• Hair loss in the treated area
• Loss of sweat and sebaceous
glandular function
2012
• Hyper/hypopigmentation

37. H&N RT: Late Effects
• Xerostomia
• Swallowing dysfunction
• Vocal dysfunction
• Laryngeal edema à necrosis
• Osteoradionecrosis (ORN)
• Hearing impairment
2012
• Visual complications

38. 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
2012 surgery involving mandible

39. Other Oral-Oropharyngeal Side-Effects
• Taste alterations
• Loss of taste, loss of appetite
– Transient but may become persistent
– Major effect on choice of food,
malnutrition, weight loss
2012

40. Dysphagia
• Field length greater than 82 mm at
second phase of Rx
• Concurrent chemotherapy
• Site
• Increasing age
2012
• All increase risk for long term
dysphagia

41. Survival Vs QOL
• EORTC QLQC-30, EORTC H&N 30
peak complaints at 2-3 months from
start of treatment
• Major problems:
– Nutrition
– Pain
2012
Head and Neck Cancer:
– Psychiatric disorders Multimodality Management
By Jacques Bernier

42. Esophageal Pathology in Patients After Treatment
for Head and Neck Cancer
• 100 patients, Mean age 64 (± 10) years;
75% were male.
• Mean time between the end of treatment and
endoscopy 40 (± 51) months.
• 81% of HNCA was advanced stage (3 or 4).
• Oropharynx (38%), larynx (33%), oral cavity
(17%), unknown primary (10%),
hypopharynx (1%), and nasopharynx (1%).
2012
Farwell et al. Otolaryng Head Neck Surg 2010 Sep;143(3):375-8.

43. Esophageal Pathology in Patients After Treatment
for Head and Neck Cancer
• Treatment modalities included
– Surgery alone (15%)
– Surgery with radiation (34%)
– Radiation alone (6%)
– Chemoradiation alone (24%)
– Chemoradiation with surgery
2012
(20%) Farwell et al. Otolaryng Head Neck Surg 2010 Sep;143(3):375-8.

44. Esophageal Pathology in Patients After Treatment
for Head and Neck Cancer
• The findings on esophagoscopy included
– Peptic esophagitis (63%)
– Stricture (23%)
– Candidiasis (9%)
– Barrett metaplasia (8%)
– Gastritis (4%)
– Carcinoma (4%)
2012 – Only 13% had a normal esophagoscopy
Farwell et al. Otolaryng Head Neck Surg 2010 Sep;143(3):375-8.

45. Esophageal Pathology in Patients After Treatment
for Head and Neck Cancer
• 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
– 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
2012
been worse had they not been on the PPI
Farwell et al. Otolaryng Head Neck Surg 2010 Sep;143(3):375-8.

46. 2012

47. 2012

48. Dose-Volume Data
• Limited
• Minimizing dose to the
pharyngeal constrictors and
larynx to < 60 Gy when possible
• Other causes – fibrosis, vascular
2012 and nerve injury

49. 2012

50. Severe acute mucositis is a surrogate risk index for long-
term dysphagia
2012

51. Osteoradionecrosis
• Bone within the radiation
field becomes devitalized
and exposed through the
overlying skin or mucosa,
persisting as a non-
healing wound for three
2012
months or more

52. Evolution of the concept of ORN
• 1983, Marx suggested etiopathology
• Endarteritis
• Tissue hypoxia
• Hypocellularity
• Hypo-vascularity
2012
• Tissue breakdown and chronic non-
healing wounds

53. Evolution of the Concept of ORN
• Suppression of osteoclast
related bone turnover is
the initial event in
development of ORN
2012
Ruggiero SL et al J Oral Maxillofac Surg 2004;62:527–34.

54. Evolution of the Concept of ORN
• 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
2012
tissue necrosis
Delanian S, Lefaix JL. Radiother Oncol 2004;73:119–31

55. 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
2012

56. Mandibular Osteoradionecrosis in Squamous Cell
Carcinoma of the Oral Cavity and Oropharynx:
Incidence and Risk Factors
• 73 patients treated for stage I - IV SCC of
the oral cavity and oropharynx 2000 -
2007
• Treatment modalities included both RT
with curative intent and adjuvant RT
2012
following tumor surgery.
Monnier Y et al. Otolaryngol Head Neck Surg. 2011

57. Mandibular Osteoradionecrosis in Squamous Cell
Carcinoma of the Oral Cavity and Oropharynx:
Incidence and Risk Factors
• Results
The incidence of mandibular ORN was 40%
at 5 years.
• Conclusions:
– Mandibular ORN is a frequent long-term
complication of RT for oral cavity and
oropharynx cancers.
2012 – Mandibular surgery before irradiation is
the only independent risk factor.

58. Factors Predictive of Severity of
Osteoradionecrosis of the Mandible
• METHODS: Retrospective analysis,
• 46 patients 2002 – 2009
• 93% had mandibular ORN, staged 0-III (Store
and Boysen).
• RESULTS: Advanced age, stage IV, RT dose,
post-RT extractions, and lack of pre-RT dental
extractions appeared predictive of severe
2012 mandibular ORN
Chopra S, et al. Head Neck. 2011 Epub ahead of print

59. 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.
2012
B.R. Goldwaser, S.K. Chuang, L.B. Kaban and M. August, Risk factor assessment for the development
of osteoradionecrosis, J Oral Maxillofac Surg 65 (11) (2007):2311–2316

60. Additional modalities
• COMPLETE RESTORATION OF REFRACTORY MANDIBULAR
OSTEORADIONECROSIS BY PROLONGED TREATMENT
WITH A PENTOXIFYLLINE-TOCOPHEROL-CLODRONATE
COMBINATION (PENTOCLO): A PHASE II TRIAL
• Conclusion:
• Long-term PENTOCLO treatment is effective, safe, and
curative for refractory ORN and induces mucosal and
bone healing with significant symptom improvement.
2012
DELANIAN S et al.Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 3, pp. 832–839, 2011

61. ORN After IMRT
• RTOG-0022 study reported an incidence
of 6% ORN in oropharynx cancer patients
treated at fraction size of 2.2–66 Gy
without chemotherapy.
2012

62. ORN After IMRT
• The University of Michigan reported on 176
patients treated with IMRT.
• At a median follow-up of 34 months, no cases of
ORN developed (attribute to conformality of
IMRT, meticulous dental hygiene as well as
salivary gland sparing )
• Similarly Studer reported a 1.3% incidence of
2012
ORN after parotid sparing IMRT

63. HBO in Treatment of ORN of
Jaws???
A systematic review in 2008 did not show value of
hyperbaric oxygen therapy for
osteoradionecrosis
Pitak-Arnnop P et al: Management of osteoradionecrosis of the jaws: An analysis of evidence. Eur J Surg Oncol
34:1123, 2008
2012
Pitak-Arnnop P et al. J Oral Maxillofac Surg.
2010;68(10):2644-5.

64. Radiotherapy Effects on Larynx
• Dysphonia and laryngeal edema are potential
long-term complications of radiotherapy for HNCa
• 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
2012
with resulting chronic dysphonia
G. Sanguineti, et al. Int J Radiat Oncol Biol Phys, 68 (3) (2007), pp. 741–749
Nguyen et al. Oral Oncol. 2011 Sep;47(9):900-4. Epub 2011 Jul 2.

65. Radiotherapy Effects on Larynx
• 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.
2012
G. Sanguineti, et al. Int J Radiat Oncol Biol Phys, 68 (3) (2007), pp. 741–749

66. Laryngeal sparing
effect of
TomoTherapy in a
patient with locally
advanced
nasopharyngeal
cancer: despite the
presence of a left
cervical node (yellow
circle) adjacent to
the larynx (red)
treated to 70 Gy,
and the area at risk
for extracapsular
extension (light
green) treated to
63 Gy, mean
laryngeal dose was
only 17.8 Gy.
2012

67. Radiotherapy Effects on Larynx
• 96 patients, median age was 55 years,
82% men.
• Primary site of cancer was
– Oropharynx 43
– Hypopharynx/larynx 17
– Oral cavity 13
– Nasopharynx 11
– Maxillary sinus 2
– Unknown primary 10
2012
Caglar HB et al. Dose to larynx predicts for swallowing complications after intensity-modulated
radiotherapy.
Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1110-8

68. Radiotherapy Effects on Larynx
• 85% underwent definitive RT and
15% postoperative RT.
• 28 patients underwent induction
chemotherapy followed by
concurrent chemotherapy,
• 59 received concurrent
chemotherapy
• 9 patients underwent RT alone.
• The median follow-up was 10
2012 months.
Caglar HB et al. Dose to larynx predicts for swallowing complications after intensity-modulated
radiotherapy.
Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1110-8.

69. Radiotherapy Effects on Larynx
• 31 (32%) had clinically significant
aspiration and 36 (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
2012 aspiration and stricture.
Caglar HB et al. Dose to larynx predicts for swallowing complications after intensity-modulated
radiotherapy.
Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1110-8.

70. Quality of Life in Patients Treated for Advanced
Hypopharyngeal or Laryngeal Cancer
• A retrospective 2-center study included 100 patients in
remission from squamous cell carcinoma, treated
between 1998 and 2009.
• 70 (24 hypopharynx, 46 larynx) treated by total
(pharyngo-) laryngectomy followed by external radiation
therapy,
• 30 (13 hypopharynx, 17 larynx) underwent an organ-
conservation protocol with concurrent radiochemotherapy
or with induction chemotherapy using platin-5FU or
taxan-platin-5FU followed by radiation therapy.
• All patients responded to the quality of life questionnaires
2012 (EORTC QLQ-C30 and QLQ-H&N35).
M. Guiberta et al. Eur Ann Otorhinolaryngol Head Neck Dis. 2011 Nov;128(5):218-23.

71. Quality of Life in Patients Treated for Advanced
Hypopharyngeal or Laryngeal Cancer
• Advanced tumor stages IVa and IVb were
significantly more frequent in the surgery groups
• In pharyngeal cancer, the only significant difference
between surgical treatment and laryngeal
conservation was for sensory disorder (taste and
odor), with better results in case of laryngeal
conservation (p < 0.0001).
• For the other items, there was a trend for quality of
life to appear better in patients with laryngeal
2012 conservation (p = NS).
M. Guiberta et al. Eur Ann Otorhinolaryngol Head Neck Dis. 2011 Nov;128(5):218-23.

72. Quality of Life in Patients Treated for Advanced
Hypopharyngeal or Laryngeal Cancer
• In laryngeal cancer, the only significant
difference was for dry mouth , which
was significantly less invalidating with
surgical treatment (p < 0.001).
• The impairment of the other quality of
life items did not differ between
surgical and conservative treatment.
2012
M. Guiberta et al. Eur Ann Otorhinolaryngol Head Neck Dis. 2011 Nov;128(5):218-23.

73. 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
2012
minimize complications.
Hauptman et al. Int J Radiat Oncol Biol Phys. 2011 in press

74. Complications After Radiation
Treatment Base of Skull
• 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.
2012
Hauptman et al. Int J Radiat Oncol Biol Phys. 2011 in press

75. 2012