OROFACIAL COMPLICATIONS

OF NON-SURGICAL CANCER
THERAPIES:DIAGNOSIS AND
TREATMENT
PRESENTER
DR ABDULAZEEZ KASSIM
DEPARTMENT OF ORAL PATHOLOGY AND ORAL MEDICINE UBTH.
25-09-2019
OUTLINE
• 1.INTRODUCTION
• 2.KEYWORDS
• 2.TYPE OF CANCER THERAPY
• 3.NON-SURGICAL CANCER THERAPIES
• 4.MECHANISN OF TISSUE DESTRUCTION
• 5.SUMMARY NOTE ON EACH OROFACIAL COMPLICATIONS.
• 6.REFERENCE
INTRODUCTION
• Oncological complication is a normal occurrence in clinical practise.
• Non surgical cancer therapy come with side effects and
complications,particularly with radiotherapy and immunotherapy.
• These complications are variable and common,affecting numerous
tissue types. This seminar will attempt to navigated the orofacial
complications,the tissues affected,the diagnosis and treatment.
• Most of these complications cannot be prevented but curative
treatment is available.if not available,supportive and palliative
management is essential for patient well being.
KEY WORDS
• 1.RADIOTHERAPY:
• This is the medical application of radiation for the clinical treatment of
human disease such as cancer.
• 2.ADJUVANT THERAPY:
• Is a therapy that is given in addition to the primary or initial therapy
to maximize its effectiveness.
• 3.NEO ADJUVANT CHEMOTHERAPY
• This is chemotherapy administered prior to surgery for the purpose of
debulking tumour
• 4.CONCURRENT/CONCOMITANT CHEMOTHERAPY:
• These are drugs administered in combination with head and neck
radiation,typically on a weekly basis throughout the duration of
treatment
• 5.INTENSITY MODULATED THERAPY:
• This is a radiotherapy technique aim at delivering radiation more
precisely to the tumour while relatively limiting the dose to the
surrounding normal tissues.
• 6.CHEMOTHERAPY
• Chemotherapy is a type of cancer treatment that uses one or more
anti-cancer drugs as part of a standardized chemotherapy regimen.
This may be given without a curative intent (which almost always
involves combinations of drugs), or it may aim to prolong life or to
reduce symptoms (palliative chemotherapy).
TYPE OF CANCER THERAPY
• There are several types of cancer therapy which are currently being
used in the management of cancer.These therapy differ according to
the type of cancer, the staging , the site of the cancer, the age of the
patient e.t.c.
• They include
• 1.SURGICAL CANCER THERAPY
• 2.NON SURGICAL CANCER THERAPY.
• Our focus on this seminar will solely be on the non surgical cancer
therapy.
NON SURGICAL CANCER THERAPY
• These include:
• 1.Radiotherapy
• 2.Chemotherapy
• 3.Immunotherapy
• 4.Hormonal therapy
• 5.Targeted therapy
• 6.Stem cell transplant
• 7.Precision medicine
MECHANISM OF TISSUE DESTRUCTION BY IN
RADIOTHERAPY
• Tissue destruction occur in radiotherapy by Cytotoxic effects and effect on the cellular
kinetics.
• 1.Cytotoxic effect: This is produced by 2 ways
A. Direct damage:
This is to DNA RNA molecules
B. Free radicals:
Radiation causing ionization of water in cells. Hydrogen peroxide
which is formed cause DNA and chromosome disruption leading to alteration in
-proteins :denaturation and impairment of enzyme function
-nucleic acids: loss of base, disruption of H-bonds between DNA strands and cross-
linking of DNA either within the helix or to other DNA, or to proteins.
• 2.Effects on cellular kinetics:
Neoplastic cells are more sensitive than normal cells especially during cell
division. Radiation of these cells will cause a reduction in size of the
population by mitotic delay which in turn inhibits progression of cells
through cell cycle and cell death during mitosis.
• The degree of tissue sensitivity to the effects of irradiation is directly
proportional to
-rate of turnover
-degree of oxygenation
-degree of differentiation
Effect of radiotheraphy orofacial tissues
Radiotherapy basically has two effect on tissues. These are
1.STOCHASTIC EFFECTS (IRREVERSIBLE)
• It is a Cumulative effects of radiation
• It is not dose dependent
• It sometimes takes years to develop
• It is often irreversible effects e.g. neoplastic transformation
2.NON STOCHASTIC EFFECTS (REVERSIBLE)
• It is a dose dependent effects that are non cumulative
• It is mostly reversible changes
Almost all oral sequelae are non-stochastic effects e.g.mucositis
MECHANISM OF TISSUE DESTRUCTION IN
CHEMOTHERAPY
• Anticancer drugs are either CYTOSTATIC or CYTOTOXIC
• Cytostatic drugs focus on the blocking of tumor cell proliferation,
while the cytotoxic drugs focus on the destruction of the cells .
• The toxic side effects are often due to involvement of collateral
tissues. These drugs include
• 1.Agent affecting multiple phase of cell cycle
• 2.M Phase inhibitors
• 3.Agent causing cell cycle independence
• 4.S Phase specific agent.
• Agent affecting multiple phase of cell cycle:
• e.g. Bleomycin,Dactinomycin,Mitomycin
• M Phase inhibitors
• e.g. Halichondrin B analogue,Taxan,Vinca alkaloids,Anthracemedione
• Agent causing cell cycle independence
• e.g. Alkyl sulfonate, Ethylenimate, Nitrogen mustard, Triazene
• S Phase specific agent
• e.g. Folate antagonist, Purine analogues, Pyrimidine
analogue,Hydroxyurea
• Collateral tissues often affected are rapidly proliferating cells in i.e
• The bone marrow
• Intestinal mucosa
• Oral mucosa
• Hair follicles and
• Gonads.
• In the oral mucosa, anticancer drugs destroy the basal cells of the
mucosal layer, and their replacement.Turnover time is affected
resulting in mucosal ulceration.
• In the oral mucosa, the progenitor cells are situated at the basal
• Layer and may be 1–3 layers depending on the thickness of the
epithelium .They follow the cyclical activity of cell division with
variable turnover time (T T).
• Turnover time (T T) is the time taken from when a cell divides to when
it passes through the entire epithelium. Turnover time is 41-57 days in
the gingiva and 25 days in the cheek. Cancer chemotherapy impairs
the turnover rate of cells including the oral epithelium leading to
ulceration.
•
• Stress, inflammation and time of the days also influences turnover
time.  Epithelial proliferation is also influenced by cytokines – TGFα
and β, IL-1, Epidermal growth factor and keratinocyte growth factor
• There are also indirect toxic effects far from the oral cavity but has a
negative effect upon it such as myelosuppression and immune cell
destruction. Salivary enzymes function is impaired particular
superoxide dismutase and peroxidase involved in the antioxidant
capacity of the gland.
• Many anticancer drugs cause damage to the DNA of cells,resulting
in mutationsand chromosomal abnormalities and seem to act as
carcinogens especially after long term treatments.
• Continuous chemotherapy poses a risk of secondary malignancy, such
as acute leukemia, arising 2 to 6 years after the beginning of the
treatment.
MECHANISM OF TISSUE DESTRUCTION IN
HORMONAL THERAPY THERAPY.
• The exact mechanism of action of these hormones is unclear,may
involve both direct effect on the tumour cells or act with an indirect
effect.
• Hormonal therapies is becoming an exciting development for
anticancer medicine. They include:
• 1.Inhibition of hormone synthesis
• 2.hormone receptor antagonist
• 3.hormone supplementation
• 4.Hormonal antibody targeted anticancer therapy
• Examples of these drugs are
• 1. ALEMTUZUMAB:
• It targets the immune system by binding to CD 52 thus inducing an immune
response
• 2.TRASTUZUMAB:
• Targets antigens on cancer cells that are involve in cell growth and
proliferation.
• 3.CETUXIMAB:
• It targets epidermal growth factor receptor(EGFR) there by inhibiting
proliferation and survival of cancer cells.
Chemotherapeutic agents
• Common chemotherapeutic agents for oral and
Maxillofacial malignancies

• Taxanes
• Cisplatin
• Fluoropyrimidines (antimetabolites)
•
Classification of orofacial manifestation of
non-surgical cancer therapy.
OROFACIAL RADIOTHERAPY HORMONAL CHEMOTHERAPY
MANIFESTATION THERAPY
ACUTE 1.Oral mucositis 1.Hypersensitivity 1.Oral mucositis
2.Infection: Fungi, reaction 2.Oral Pain
bacteria 2.Mucositis 3.Oral ulceration
3.Salivary gland 3.Salivary gland hypo 4.Bleeding
dysfunction: function.
sialadenitis 4.Developmental
xerostomia disturbance
4.Taste dysfunction

CHRONIC 1.Mucosal 1.Osteonecrosis of

fibrosis/atrophy the jaws
2.Xerostomia:Halitosi 2.Infection
s,dental caries 3.Lichenoid reaction
3.Soft tissue necrosis 4.Dental abnormality
4.Osteonecrosis 5.Salivary gland
5.Taste dysfunction: impairment
dysgeusia,ageusia 6.Taste disturbance
6.Muscular/ 7.Neurotoxicity
cutaneous fibrosis 8.Oral pigmentation
7.Infection: Fungal, 9.Steve-Johnson
bacteria,virus syndrome-toxic
8.Secondary epidermal necrosis.
malignancies. 10.Abnormal facial
development
.
Percentage distribution during radiotherapy
treatment(National cancer institute Bethesa
2002)
• Salivary gland hypofunction/xerostomia - 81%
• Dysgeusia - 66.5%
• Candidiasis - 39.1%
• Oral pain - 33%
• Trismus - 25.4%
• Dental caries - 24%
• Osteoradionecrosis - 7.4%
Orofacial complications of nonsurgical cancer
therapy
CATEGORY TISSUE ORAL COMPLICATION
1.TISSUE SPECIFIC MANIFESTATION MUCOSAL 1.Mucositis
2.Anemia-related mucosal
changes:atrophy,burning and
paleness
3.Neutropenic ulcer
4.Lichenoid erythema and ulcer
5.Pyogenic granuloma
6.Chemotherapy associated
pigmentation
7.Targeted therapy-associated
stomatitis
8.Hyperpigmentation

SALIVARY GLANDS 1.Salivary hypofunction

2.Sialoadenitis
3.Mucocele
MUSCULOSKELECTAL 1.Osteoradionecrosis
2.Drug induced osteonecrosis of
the jaw
3.Impaired mastication
4.Swallowing disorders
5.Speech disorder
6.Fibrosis+Scaring+Trismus(Limited
neck and shoulder mobility)
7.Loss of elasticity, reduced range
of motion and limited mouth
opening(scleroderma-like
features)

SENSORY DISTURBANCE Dysgeusia

Neuropathy
Tooth hypersensitivity

TEETH AND GINGIVAE Demineralization and caries

Gingival enlargement/inflamation
2.NON-TISSUE SPECIFIC INFECTION Viral
MANIFESTATION Bacterial
fungi

MALIGNANCY Squamous cell carcinoma

Post radiation sarcoma
Post transplant lymphoproliferative
disorder.

DEVELOPMENTAL Abnormal teeth development

Altered eruption pattern
Craniofacial synostosis

BLEEDING Thrombocytopenia
Disseminated intravascular
coagulopathy.
1.ORAL MUCOSITIS
• It is a very common painful inflammatory reaction of the oral mucosa. This
is characterized by infiltration of the inflammatory cells followed by
epithelial disruption and ulceration.Oral mucositis appears 4-7 days after
the initiation of chemo and disappears 2-4 weeks after the treatment is
completed.
• Drugs commonly implicated in oral mucositis are
• Doxorubicin, Bleomycin, Fluorouracil,or Methotrexate
• TYPES
• 1.Persistent type: Lesions do not heal within 3 months
• 2.Recurrent type: New discrete ulcer wax and wane following radiotherapy
Clinical features
• Appears 7-10 days after chemotherapy. The 1st sign is erythema,
followed by a burning sensation,eodema and ulceration are present
and affect basic functions such as speech, swallowing, and eating.
• At the peak, there is deep ulceration and severe pain.
• Ulcers regress in 2-3 weeks after treatment is over leaving no
scar.Ulcer are covered by pseudomembrane with poorly defined
outlines common on the buccal and labial mucosa,lateral surface of
the tongue,floor of the mouth and the soft palate
Risk factors for oral mucositis
• 1.Higher dose and frequency of the drug
• 2.The type of agent/Drugs that affect DNA syntheses such as antimetabolites
(methotrexate,5-FU& purine analogs)increase the incidence of oral mucositis
up to 60%.
• 3.Methotrexate and etoposide are secreted in saliva which favours oral toxicity.
• 4.Older age,malnutrition,pre-existing medical problems,poor oral
health,trauma,liver disease,and kidney functional status
• 5.Periodontal dx where Porphyromonas gingivalis,fungi and viruses cause
ulceration and mucositis.
• 6.Gene mediated polymorphisms of TNF-a
Diagnosis
• This is made from history and site specific lesions associated with the
therapy within 4-7 days following the therapy.
• The differential diagnosis includes
• Infection
• Drug eruption
• Trauma from restorative material
• Neutropenic ulcer.
• Graft versus host disease
Treatment
• 1.Good oral hygiene
• 2.Avoidance of spicy, acidic,hard and hot foods and beverages.
• 3.Use of mid-flavoured toothpastes
• 4.Bland rinses:
• Saline mouthwash
• (1 teaspoon of salt mixed with 500ml of lukewarm water)
• Sodium bicarbonate mouthwash
• (2 teaspoon of sodium bicarbonate in 500ml of lukewarm water)
• Saline and sodium bicarbonate mouthwash (in 1 cup (250mls) of
lukewarm water dissolved in ¼ teaspoon of bicarbonate+1/4
teaspoon of salt)
• 5.Topical anaesthesia (gel,ointment or spray)
• 6.Lozenges (Dyclonine lozenges 1.2,2 or 3mg ) repeated after 2 hours
if necessary.
• 7.Analgesics: Benzydamine HCL topical rinse,Tantum oral rinse 15ml
• 1-3 hourly for not > 7 days.
• 8.Growth factor: (Keratinocyte growth factor-1)
• PALIFERMIN
• It decreases the incidence and duration of oral mucositis in patients
• undergoing high dose chemotherapy with or without radiotherapy
• followed by bone marrow transplant for hematologic cancers.
• KEPIVANCE 60mcg/kg/day,administered as an intravenous bolus
• injection for 3 consecutive days after myelotoxic therapy,for a total
• 6 doses.
• UPDATED GUIDELINE FOR THE PREVENTION AND TREATMENT OF
MUCOSITIS (American society of clinical oncology 2007)
• 1.Basic oral care:
• use of soft tooth brush that is replaced on a regular basis
• 2.Pain control:
• Morphine was preferred as the analgesic of choice
• 3.Radiotherapy:Prevention
• Use of midline radiation blocks and 3-dimensional radiation treatment
to reduce mucosal injury.
• 4.Prevention of radiation induced mucositis:
• Benzydamine was recommended for prevention of radiation induced
mucositis in patient with head and neck cancer receiving moderate-
dose radiation therapy
• 5.Chlorhexidine should be avoided
• 6.Antimicrobial lozenges should be avoided.
• 7.Treatment:
• Keratinocyte growth factor-1(Palifermin) was recommended for oral
mucositis associated with stem cell transplant
• Amifostine for radiation procticitis
• Cryotherapy for high dose Melphalan-induced mucositis
• Cytofos Vial: its given before radiotherapy(200mg/m square BSA once
daily infusion given over 3minutes,15-30mins before radiotherapy.
2.NEUROPATHY
• These can be tooth neuropathy and orofacial neuropathy.it is usually
reported in patient treated with cytotoxic such as vinca plant
alkaloids,taxanes,bortezomib and platinum derivatives.
• It is characterised by non specific neuronal hyperactivity.examples
include
• 1.Oral neuropathy pain
• 2.Dental neurotoxicity
• 3.Perioral neurotoxicity (Thalidomide associated)
• 4.Dysesthesis (Tyroxine kinase inhibitor associated)
• ORAL NEUROPATHIC PAIN:
• Oral pain is commonly seen in cancer patient undergoing both chemotherapy
and radiotherapy.The pain is usually due to tissue injuries following
radiotherapy.IT IS TYPICAL DESCRIBED AS BURNING,”PINS AND
NEEDLES’’,NUMBNESS AND TINGLING OF THE AFFECTED AREA. usually no lesion
is seen in the area.
• Diagnosis is usually by the history and by pain assessment tools.
• Pain management in head and neck radiotherapy is
• Treatment:
• 2% morphine mouthwash in head and neck radiation therapy,or 0.5% doxepin
mouthwash.
• DENTAL NEUROTOXICITY
• This is a rare condition that was reported after cyclophosphamide use.the
pain was characterised as severe,throbbing tooth ache,with no clinical or
radiologic abnormalities.palliative pulp extirpation relieved the pain,and the
histologic evaluation of the pulp excluded inflammation or malignant cell
infiltration.
• Diagnosis
• Its usually from history,clinical features and histologic evaluation of the pulp.
• Treatment:
• Palliative pulp extirpation relief the pain
3.ORAL INFECTION:

• Chemotherapy related oral infections,which account for 25-50% of

the total infections,contribute significantly to the morbidity and
mortality in these patient.
• The infection in radiotherapy is minimal.Herpes simplex infection is
the most common infection in patient undergoing radiotherapy.
• Susceptible areas include teeth,gingiva,salivary glands,and mucosa.
• It should be noted that in myelosuppressed patient,the cardinal signs
of infection(erythermal and swelling are not always present).
• Therefore ,the more reliable indicators such as fever,pain and the
appearance of lesions should be used to closely monitor all suspected
cases.
• The opportunistic organism usually found are:
• Staphylococci,streptococci,klebsiella pneumonia,pseudomonas
aeruginosa and Escherichia coli.
• These may cause acute exacerbations of pre-existing periodontal or
periradicular infections when the granulocyte count dips below
1000/mm.
• For patient receiving head and neck radiotherapy alone the weight
prevalence of clinical fungal infection was
• 7.5% pre-treatment
• 39.1% during treatment
• 32.6% after the end of radiation treatment
• The most common form of intraoral candidiasis reported in oncology
patient are pseudomembranous and erythematous candidiasis.
• This is sometimes associated with burning mouth syndrome and
altered taste.
• The most dangerous complication in the realm on infections comes
from fungal species.The mortality rate of systemic fungi infection are
higher.Other infections include viral infections (Herpes simplex
virus,varicella zoster virus and cytomegalovirus)
• DIAGNOSIS:
• Diagnosis is made from History,clinical appearance of lesion and culture
of pathogenic organism.
MANAGEMENT:
• Treatment is usually with antimicrobial,antifungi and antiviral drugs
depending on the clinical presentation.
4.SALIVARY GLAND HYPOFUNCTION
Ionizing radiation result in cell damage,death and subsequent fibrosis
of salivary glands.Does as low as 20Gy will result in sparse thick ropy
saliva.in particular,if the parotid gland are in a field which received
40Gy or over, permanent dysfunction of the salivary glands should be
expected and discussed with the patient prior to treatment.
• PREVENTION
• 1.Intensity modulated radiation therapy.
• 2.use of Amifostine (protects tissue against the harmful effect of
radiation)
• CLINICAL SIGNS AND SYMPTOMS OF HYPOSALIVATION
• These signs can be made manifest in the following tissues
• 1.teeth
• 2.oral mucosal
• 3.tongue
• 4.lips
• 5.oral cavity
• 1.TEETH
• -Increased incidence of dental caries
• -Enamel demineralization(chalky spots at the cervical region of teeth)
• -Enamel erosion and attrition
• -increased plaque accumulation
• -increased tooth hypersensitivity
• 2.ORAL MUCOSAL
• -Mucositis
• -mucosal desquamation
• -Atrophic mucosa
• -Allergic or contact stomatitis and lichenoid lesions(mostly opposing
metal restorations)
• -Recurrent oral candidiasis
• -Traumatic ulcerations on the lateral border of the tongue, the buccal
mucosa or both
• -Painful or burning mouth(intolerance to spicy,sour or salty food and
drinks)
• -Nonspecific gingival inflammation and generalized oral erythema.
• ORAL CAVITY:
• Oral allergic or contact reactions
• Halitosis
• Dysphagia
• Plaque accumulation
• Dysgeusia.
• DIAGNOSIS:
• This require careful evaluation of signs and symptoms,with clinical extra-oral
and intra-oral examinations,assessment of salivary gland function by measuring
resting and stimulated flow rates and in some cases,biopsy of minor salivary
glands.
• Normal saliva production is
• Unstimulated flow: 0.2-0.5ml/minute
• Stimulated flow: 4-5ml/minute
• An unstimulated salivary flow of less than 0.1ml per minute and stimulated
whole salivary flow of below 0.7ml is suggestive of salivary gland hypofunction.
• TREATMENT:
• Treatment of salivary gland hypofunction and xerostomia induced by
radiation therapy is primarily symptomatic.alleviation of xerostomia
include
• 1.Patient education
• 2.Frequent sipping of water.
• 3.The use of saliva substitute (hydroxyethylcellulose or
carboxymethylcellulose)
• 4.The stimulation of salivary gland e.g. Pilocarpine hydrochloride 5mg 4
times daily or Cevimeline 30mg 3 times/day can also be used.
5.TASTE ABNORMALITY (DYSGEUSIA)
• Chemotherapeutic agent such as:
cyclophosphamide,dacarbazine,doxorubicin,5FU,Methotrexate,Nitrog
en mustard,cisplastin,and vincristine frequently damage the taste
buds causing taste alteration (Camp-sorrel,2005).
• Cancer therapy patient may experience a metallic or chemical taste
when chemotherapy is delivered and this is consistent with drug
secretion in saliva (Epstein and Barasch, 2010).
• DIAGNOSIS
• This is made from history and clinical presentation.
• MANAGEMENT OF DYSGUESIA
• Currently, no guidelines exist for the pharmacologic management of dysguesia.
• The American institute for cancer research(2010) suggest the following for
improving the flavour of foods:
• 1.Consume food that are cold or at room temperature
• 2.Avoid the use of metallic silverware.
• 3.Add more seasonings and spices to foods,such as salt, oregano, basil,
cinnamon, and ginger.
• 4.Add sugar to decrease salty or bitter tastes.
• 5.Choose frozen fruits such as melon balls, grapes or oranges.
• 6.Choose more bland foods
• 7.Suck on hard, sugarless candies.
• 8.Drink more water with meal to help with swallowing or rinse away
• bad taste.
• 9.Eat small meals several times a day.
• 10.Frequent oral hygiene are adviced.
6.OSTEORADIONECROSIS
• Is a rare condition of non vital bone in site of radiation injury.ORN can
be either spontaneous or the result of an insult.symptoms include,but
are not limited to
• 1.Pain,swelling,or infection of the gums
• 2.A sore, or ulcer, in the mouth or on the jaw
• 3.Trismus
• 4.Loss of sensation in the area
• 5.Jaw fracture not related to an accident or other trauma
• 6.Exposed bone inside the mouth.
• MANAGEMENT OF ORN
• Management of ORN is based on prevention that begins with a
comprehensive oral and dental care before radiation therapy and a
close follow-up post radiation.
• Medical therapy:
• This treatment of ORN is primarily supportive, involving nutritional
support along with superficial debridement and oral saline irrigation
for local wounds.
• Antibiotics are indicated only for definite secondary infection.
• Hyperbaric oxygen:
• Hyperbaric oxygen therapy is commonly recommended to prevent
ORN,but clinical efficacy is inconclusive.
• Depending on where the osteoradionecrosis develops and how far it
progresses, the treatment may vary from sequestrectomy to resection.
• DIFFERANTIAL DIAGNOSIS
• Medical related osteonecrosis of the jaw (MRONJ):
• First described in 2003.Associated with Antiresorptive drugs
(Biphosphonate ,Denusomab )
• The risk for MRONJ increase with the duration of treatment with the
relevant medications and associated factors e.g. old age, diabetis mellitus,
smoking, dentoalveolar procedure.
• Incident of MRONJ range from 0.7% to 6.7%.
• Following extraction, the incidence is 1.6% to 14.8%
• DIAGNOSIS
• It is base on history and clinical presentation
• TREATMENT
• Treatment is tailored individually according to symptom severity and patient
medical status.(it include both medical and surgical management)
CONCLUSION
• Oral manifestation of non surgical cancer therapy is currently
inevitable.This makes oral care an important part of the overall cancer
management.Once cancer is diagnosed, the oral oncologist should be
involved as part of the management team In the treatment
planning,management and follow up of the cancer patient.
• Most oral complications can not be effectively prevented but their
management and patient satisfaction is possible.
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