1. health and fitness
2. disease
3. cancer

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The delayed effects
of disease and treatment
interventions on individuals who
have had Head and Neck Cancer
Welcome to the National Study Day 2013
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This Head and Neck Cancer Study Day Aims
– To provide time to reflect on practice
– New information on old issues
– Provide updates on areas which will impact on our
patient population
– Question current ways of working
– Network with others in the field
– Inspire and motivate
Enjoy your day
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“I felt as if my illness were
a blanket the world had
thrown over me; all that
could be seen from the
outside was an
indistinguishable lump”
(Lucy Grealy 1994)
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Managing the complexity of ‘Oral
Mucositis’ and potential Oral
Complications for individuals who have
treatment for a head and neck cancer
Sonja Hoy
Clinical Nurse Specialist Head, Neck
Thyroid and Radiation Protection
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A Neglected Task
Despite its acknowledged
importance, oral care is one of the
first things to be set aside when
workloads are excessive
(McGuire 2003)
The mouth is an important aspect of
cancer care, all too often this
aspect of care may be overlooked
until problems arise. This leads to
needless distress and discomfort
and in some cases serious clinical
consequences.
(European Journal of Cancer Care
2009)
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A study in 2002 by Rose-Ped and colleagues
conducted 33 interviews of patients who had
completed radiotherapy for Head and Neck cancer
reporting Oropharyngeal Mucositis as the most
debilitating side effect.
(Cancer Nursing 2002)
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Aim of the session
– A greater understanding of Oral Mucositis and its
aetiology
– Understanding the morbidity for the individual
experiencing Oral Mucositis
– Recognition the acute and delayed effects of
treatment on the oral mucosa
– Strategies that may influence care and follow-up after
treatment
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How we can define Oral Mucositis
As an inflammation of the mucosal membrane, characterised by
ulceration resulting in severe discomfort and pain, dysphagia, impairs the
individual’s ability to talk, eat and swallow. Mucosal injury provides an
opportunity for infective agents to flourish placing the individual at risk
of bacteraemia and sepsis ( Rubenstein, Peterson, Schubert, Keefe,
McGuire, Epstein, et al, 2004).
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What are the statistics?
• Incidence of OM in head and neck cancer patients quotes
mean incidence of 80% (Trotti 2003, Worthington et al
2006)
• Remains under reported
• It is under appreciated by some health care professionals
(Moutesim & Tappuni 2008)
• The effect of Oral Mucositis on the individual is profound,
debilitating and can lead to treatment interruptions and
hospitalisation
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What are the main chemotherapy agents that alter the
mucosal tissue?
– 5FU bolus causing more mucotoxic damage than
infusion regimes
– Docetaxel
– Doxorubicin
– Cyclophosphamide
– Methotrexate (folinic acid rescue)
– Melphalan
– Begins around 4 to 5 days post chemotherapy lasting
for about 5 days (Sonis 2007), Sonis et al 2004)
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Radiotherapy impact on mucosal tissue
– Changes to the oral mucosa are seen after only an
accumulated dose of 10Gy
– In most cases ulceration is seen at 30Gy the end of
only the 3rd week or middle of treatment for Head and
Neck Cancers
– Continues for up to 6 weeks post completion of the 6
weeks of treatment
– Tonsil and base of Tongue tumour sites have a large
area of the mucosal tube irradiated
– Those receiving chemotherapy and radiotherapy are
at significant risk of developing OM (Sonis et al 2004,
Sonis 2007)
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Pathobiology of Mucositis
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Normal Mucosal Epithelium
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Historic Pathobiologic view of Oral Mucositis
– Based on the views that cytotoxic treatments kill
rapidly dividing cells; like those in the renewing
epithelium
– Thus leading to an imbalance in the equilibrium of
epithelial loss and replenishment (Keefe et al 2007)
– Once enough damage to the epithelium occurred to
thin it to breaking point ulceration occurred
– Bacterial colonization, secondary infection was
thought to contribute to ulceration and its continued
development, duration impacting on healing
– Approaches were then developed on the view that
Oral Mucositis had an infectious aetiology
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What is the new evidence?
– Early tissue damage using morphological evidence from
histology and electron microscopes identified that early damage
was seen in the sub-mucosa before any clinical signs
– This corresponds with patient reported symptoms without any
visible signs clinically
– So what was happening in the sub-epithelial tissue was
apoptosis of fibroblasts and micro-vasular endothelial cells not
dying epithelium
– Therefore microscopic damage is occurring much earlier than
clinically detectable damage to the epithelium
– Signalling from the damaged sub-mucosa cells to the epithelium
mediates (communicates) epithelial damage/injury
– The endothelium or sub-mucosa acts as a foundation both
physically and bio-chemically to the epithelium. When the
foundation is lost then the epithelium collapses
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Oral Mucositis
A final common pathway...
Normal
epithelium
Phase 1
Initiation
0-2 Days
Sonis S et al. Cancer 2004;100:(9 Suppl):1995–2025
Phase 2/3
Messaging,
signaling,
amplification
Phase 4
Ulceration
(mucositis)
Phase 5
Healing
2-10 Days
10-15 Days
14-21 Days
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Cytokines in the development of Oral
Mucositis
– Increases in pro-inflammatory cytokines are associated with the
development of Oral Mucositis
– They play important roles in mediating injury and in signalling
pathways
– Pro-inflammatory cytokine levels such as tumour necrosis factor
(TNF), interleukin 6 (IL-6) and interleukin-1beta (IL-1B)
increase before tissue damage is apparent
– Much of the tissue damage seen is due to the consequence of
apoptosis
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Apoptosis (cell death)
– Apoptosis is seen as a result of chemotherapy and radiotherapy induced
damage within the sub-mucosa
– Enhanced apoptosis exacerbates the risk of Oral Mucositis
– The data seems to suggest the idea that apoptosis and its regulation are
critical factors in the development of Oral Mucositis
(Paris et al 2001)
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Patho-physiology
– Initiation of tissue damage (Chemotherapy and or
Radiotherapy treatment)
– Upregulation of inflammation (Apoptosis)
– Signalling and amplification (Cytokine activity)
– Ulceration and infection (damage to the submucosa
and collapse of the epithelium)
– Healing
(Sonis 2007)
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Mucosal Damage:
a Complex Biological Process
Adapted from Sonis ST. Cancer. 2004;100(suppl 10):1995-2025.
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Initiation
– Occurs immediately after the administration of radiation or
chemotherapy. Therefore in radiation treatment initiations
events are chronological
– Direct damage to DNA can cause immediate cell death in the
basal epithelia and sub-mucosal cells
– The chemotherapeutics and ionising radiation generate reactive
oxygen species (ROS) that damage connective tissue, DNA, and
cell membranes; stimulate macrophages and a cascade of critical
biologic mechanisms, molecules and pathways. (Sonis 2007)
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Primary Damage Response
– Activation of a number of signalling pathways from
chemotherapy and radiation, damage cells
– These damaged cells with their damaged DNA
indirectly precipitate the beginning of the biologic
process that results in mucosal injury (Sonis 2007)
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Signal Amplification
– Multiple sources of damage leads to message generation
activating normal damage response pathways
– Many of the proteins produced during this primary damage
response stimulate additional injury through positive feedback
loops. TNF activates NF-xB, NF-xB initiates nitrogen-activated
protein kinase (MAPK)
– Feedback loops magnify the response and prolong damage by
continuing to provide signals for days after primary injury
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Ulceration
– At this stage we clinically see the significant damage/ injury
– The ulcerations are deep, broad and painful
– Visuably they are covered with a pseudo membrane made up of dead
cells and fibrin
– This is then a very desirable environment for secondary infections
commonly gram +ve and gram –ve organisms
– They can then invade the submucosa and cause bacteremias
– In patients with altered WBC then there is significate risk of sepsis
– This process also initiates macrophage pro-inflammatory cytokine
production (amplifying the situation)
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Oral mucosal damage and infection
– The mouth’s mucosa is a rich environment of
bacteria, fungi and viruses
– A portal of entry into the body
– Awareness that specific oncology patients are at risk
the elderly and children along with those which have
an altered neutropenic status (Sonis et al 2007, Keefe
et al 2007)
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Healing
– This is the least understood phase
– Starts to resolve spontaneously about 2-3 weeks after treatment
– Cyclooxygenase (COX-2) expressed by the fibroblasts and
vascular epithelium may play a role in rebuilding the submucosa as it potentates angiogenesis
– This signals and end of the ulcerative stage
– After repair it is interesting that the epithelium or the structure
of the sub-mucosa is not the same state pre mucotoxic damage
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What are the potential opportunities for
understanding the pathobiology of mucositis?
– With increased understanding of the signalling pathways involved in
the development of Mucositis it is allowing us to identify potential
therapeutic targets
– We must ensure that any interventions protect ‘normal tissues’ whilst
avoiding the protection of cancer cells
– Greater understanding of the patho-biology of Mucositis will improve
the effective use of targeted treatments by understanding what the
cellular interactions are
– In time we maybe able to tailor treatments regimes with effective
prophylaxis and interventions to treat OM
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The Physical impact of Oral Mucositis
• Experiencing mild discomfort to fluid and foods to actual
trauma and pain
• The domino effect of oral pain leads to poor oral care,
alteration to communication, poor hydration and nutrition
• Open ulcerated areas, tenacious mucus and alteration to
salivary function increases risk of nausea and vomiting,
local and systemic infection
• Increases in anxiety and fatigue
• Further damage and pain if N&V is not controlled
• Altered biochemistry can be compounded by Cisplatin
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The Psycho-social impact of Oral Mucositis
• Impact on individual enjoy-ability and QOL associated
with food
• Sharing a meal or drink are an integral part of socialising
experiencing loss, anger…
• Disengagement in what is seen as everyday activities of
living, increasing social isolation (Rubenstein et al 2004)
• Fear around individual appearance a visual disclosure of
disease
• Impact on verbal communication
• Frustration, anxiety and depression (Wong et al 2006)
• Financial and economic burden of treatment and recovery
(Lalla et al 2006)
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What are the key interventions ?
– Basic oral hygiene assessment and care planning (Keefe et al
2007)
– Nurses leading oral care, oral assessment and education
– Initial dental assessment, extractions with an established hygiene
protocol, with a hygienist throughout and post treatment
– Smoking cessation planning involvement of community teams
(DOH, WHO and improving clinical outcomes data)
– Alcohol detoxification prior to commencement of determined
modalities
– Tailored educational interventions (Armstrong & McCafferty
2006)
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Assessment
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Pre-treatment morbidity factors
•
•
•
•
•
•
•
•
•
Poor oral hygiene and poor nutrition
Smoking and/or Alcohol intake
Age
Planned treatment pathway
Other medications
Oxygen therapy
Co-morbidities
Educational status
HPV status
These may impact on severity and length of Oral Mucositis
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Recommendations- Smoking
– Increased risk of progression/recurrence if continue smoking
after treatment
– Poorer outcomes in survival in those that smoke prior to
diagnosis
– HNCa patients that carry on smoking during Radiotherapy
found to suffer from mucositis for average of 23.4 weeks in
comparison with 13.6 weeks in the non-smokers, (Webb, 2008)
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Dentate Patients
– Pre treatment dental assessment
– Encourage regular dental check ups
– Antibiotic cover required for extraction if within XRT
field
– Fluoride crucial for dentate patients
– Brush with pea sized amount of fluoride toothpaste
– Saline or salt water rinses
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Edentulous Patients
–
–
–
–
–
–
Examine oral cavity with dentures removed
Inspect dentures over a sink of water
Scrub with nail/toothbrush & soap daily
Remove dentures & rinse with water after meals
Soak dentures overnight in water
If oral infection present, soak dentures overnight to
disinfect
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World Health Organisation (WHO)
– Most widely used instrument
– Addresses all 3 components of OM
– Objective signs (ulceration)
– Subjective symptoms (pain)
– Functional disturbances (inability to eat)
– Widely regarded as the gold standard
– Never been tested for reliability
– The tool we use in daily practice at Christie
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Assessment of Oral Mucositis
Mucositis Grade
Scale
0
1
WHO
Oral
Toxicity
1
Scale
None
Soreness
and
erythema
2
Erythema,
ulcers,
patient can
swallow
solid diet
3
4
Ulcers,
extensive
erythema,
patient
cannot
swallow solid
diet
Mucositis to
extent that
alimentation
not possible
WHO = World Health Organization
World Health Organization.
Handbook for reporting results of cancer treatment. 1979;pp. 15-22.
1
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Oral Assessment
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Erythema – No
Pain – Yes
Diet - Solids
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Erythema –
Yes
Pain – Yes
Diet - Solids
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Erythema –
Yes
Pain – Yes
Diet - NPO
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Erythema –
Yes
Pain – No
Diet - Solids
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Erythema –
Yes
Pain – Yes
Diet -NPO
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Erythema –
Yes
Pain – Yes
Diet - NPO
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Erythema – No
Pain – No
Diet - Solids
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Erythema – No
Pain – Yes
Diet - Solids
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Erythema –
Yes
Pain – Yes
Diet - Liquids
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Erythema –
Yes
Pain – Yes
Diet - Liquids
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So what are the products out there in the literature?
–
–
–
–
Allopurinol mouth washes
Immunoglobulin’s
Human placental extract
Bendzydamine HCL (Cheng et al 2006). Kazemian et al 2009 study reduced grade 3
mucositis from 78.6% in placebo group to 43.6 % in the Bendzydamine arm (Diffllam
oral rince). Is a NSAID and stops the release of prostaglandins after tissue injury
– Sucralfate contra-indicated in Head and neck setting
– Chlorhexidine and Tetrachlorhexidine for dental health not Oral Mucositis
– Magic mouth wash (lidocaine solution, dipenhydramine hydrochloride, aluminium
hydroxide suspension)
– Saline
The Cochrane review concluded that RCT multi-centre studies were needed to determine
efficacy and best practice
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The old and the new products
– Caphosol: prevention and treatment, rich in both calcium and
phosphate ions. It works by lubricating the mouth - keeping it clean
and moist - and making food easier to swallow (Miyamoto et al 2009,
Haas et al 2008)
– Mugard: prevention and treatment is a viscous, mucoadhesive rinse
which provides a protective coating to the oral mucosa
– Oralbase
– Amifostine: issues around its radio-protection activity and protection of
tumour cells (Grau et al 2004)
– Pilocarpine used for late effect xerostomia (Grau et al 2004)
– Biotene products
– Artifical saliva: AS Saliva Orthana, Biotene oral balance, Bioxtra,
Glandosane, Luborant. Newer products are Zerotin and Aquaoral
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Treatment of Therapy-Induced Mucositis from the UKOMIC group
Grade 1 or 2 Mucositis
–
–
–
–
–
–
–
Ensure oral hygiene is adequate. Consider increasing the frequency of saline rinses.
Consider the need to remove dentures if they are irritating.
Closely monitor nutritional status and refer to dietician if eating and drinking are
affected.
Provide simple analgesia, which may include soluble paracetamol 1 g four times daily
(two tablets should be dissolved in water and used as a mouthwash). It should be
remembered that paracetamol may mask fever.
Escalate to soluble co-codamol 30/500 if required. The use of NSAIDs is
contraindicated due to the risk of bleeding and renal impairment (Keefe et al., 2007).
Consider benzydamine 0.15% oral solution (Difflam®), 10 ml rinsed around the mouth
and spat out. Repeat between every 1.5 to 3 hours, as required. If the patient complains
of stinging, dilute 10 ml of Difflam® with 10 ml of water prior to administration and
use 10 ml. However, this may be poorly tolerated in patients receiving head and neck
radiotherapy and in any patient with severe mucositis.
Check to see if the patient has evidence of oral infection and if so ensure an antiinfective agent is prescribed
Consider Caphosol® (4–10 times a day) to prevent grade 1 and 2 OM becoming more
severe.
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Treatment of Therapy-Induced Mucositis from the UKOMIC group 2012
Grade 3 or 4 Mucositis
In addition to the recommendations for grade 1 and 2 OM, the
following should
be considered:
– Use of stronger analgesia, including Oxynorm®, Sevredol® and
Oramorph® to alleviate pain (Oramorph® may sting mucosa due to its
alcohol base). If patients continue to suffer from pain from mucositis,
consider using further opioid analgesia, such as fentanyl patches,
patient-controlled analgesia or a syringe driver (seek advice from the acute
pain team or the palliative care service). Laxative medications should be
prescribed to prevent constipation and associated nausea.
– Ensure intravenous and/or enteral hydration and feeding
is prescribed, as oral intake may be reduced (following
consultation with the dietician).
– Consider Caphosol® (4–10 times a day).
– Consider applying a coating protectant, e.g. Gelclair®,
MuGard®, Episil®. The product should be rinsed around the
mouth to form a protective layer over the sore areas,
and generally applied 1 hour before eating.
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The potential oral complications after
treatment
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Physical issues post radiation therapy
–
–
–
–
–
–
–
Xerostomia and Hyposalivation (Haas & McBride2011)
Dental Caries
Peridonal disease
Dygeusia: Taste changes (Consider Zinc therapy)
Persistant dysphagia (refer to SALT)
Dysphonia
Trismus can range from 10-40% of patients and increases the risk of
aspiration due to the restriction of the muscles used to breakdown food
(Carper 2007)
– Fungal Infections
– Osteoradionecrosis
Epstein et al 2001 reported a dry mouth moderate to severe in 70 % of
patients post treatment
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Xerostomia
“The challenge is for
practitioners to revise the
mundane through reflection
and to review it as the
sacred”
(Freshwater 1998)
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The salivary glands
– In addition to small salivary glands, there are three large salivary
glands, including the parotid glands, submandibular glands, and
sublingual glands on each side of the mouth
– Saliva serves to maintain oral moisture, to reduce tooth decay, and to
assist in digestion
–
Besides, saliva acts as a natural neutralizer of stomach acid when it
refluxes into the oesophagus
– Main salivary glands Parotid, sub-mandibular and sub-lingual produce
approximately 80% of saliva and this is produced within seconds from a
stimuli; smell, taste and sight
– Parotids produce the serous component while the other minor glands produce
the mucus
– We normally produce 1-1.5 litres of saliva per daily (Cheng et al 2004)
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Xerostomia
– Defined as dry mouth resulting from reduced or
absent saliva flow
– A well know side effect of radiation to the head and
neck (Haas & McBride 2011)
– A possible side effect of a wide variety of medications
and may or may not be associated with decreased
salivary gland function
– What is interesting is Xerostomia is a common
complaint affecting approximately 20 percent of the
older adult population, however it maybe older adults
often have a variety of medications and the side effect
of these may be Xerostomia
– (Cathy L. Bartels 2000-2013 OCF Montana)
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Saliva substitutes do not stimulate saliva
• Glandosane® (Kenwood/Bradley) spray
• Xerotin ® spray (SpePharma)
• Saliva Substitute® (Roxane Labs) liquid
• Salivart® (Gebauer) preservative-free aerosol
• Salix® (Scandinavian Natural Health & Beauty) tablets
• V. A. Oralube® (Oral Dis. Res. Lab) sodium-free; liquid
• Xero-Lube® Artificial Saliva (Scherer) sodium-free; spray
• Biotene® Gentle Mouthwash
• Biotene® Dry Mouth Gum
• Oralbalance® Long-lasting Moisturizing Gel
• Biotene® Dry Mouth Kit
• Biotene® Dry Mouth Toothpaste
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The Psycho-social impact of Oral Mucositis
•
•
•
•
•
•
Independence vs dependence
On going side effects remind patient of their disease
Social isolation versus socialisation
Impact on intimacy, sexuality and relationship changes
Treatment many weeks; recovery is many months to years
Cyclical anticipation issues due to the expected mucositis and or expected and
experienced pain
(Haas & McBride 2011)
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What is the way forward?
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Continue with the interventions we have available
today
– Imaging prior to commencing treatment
– IMRT
– Removal of any teeth that may show signs of peridontal disease prior
to EBRT; at least 14 days between extractions and starting treatment
– Life long use of fluoride (trays or high fluoride tooth paste)
– Life long commitment to strict oral hygiene
– Oral hydration
– Pharmacology products for xerostomia
– Acupuncture
– Therabite jaw rehabilitation (Haas and McBride 2011)
– Anti-fungal therapy
– Education and empowering the patients
– Community facilities for Nurses, Dieticians and SALT
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Thinking beyond 2013….
The wider context:
–
–
–
–
–
–
–
Collaboration of interventions and supportive care (de Castro & Guindalini 2010)
National Guidance and standardisation for OM (see EONS 2011, UKOMIC 2012)
Audit and research (Worthington et al 2006, Harris et al 2008)
Randomised controlled multi centre studies
Honesty about the limitations of managing OM
Adequate pain relief during treatment and recovery
Utilising other methods to identify at risk patients who may require early and
prolonged interventions e.g. HAD scale, FACIT assessment tool, distress thermometer,
oral assessment tools and protocols (Harris et al 2008, Hogan 2009, Hass & McBride 2011)
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... how?
– Collaboration with HCP and challenging the boundaries of
care
– Rationalisation of resources: establishing what resources we
have and how best they can be utilised (Wells et al 2007)
– A greater political voice about oral care and cancer care
(political targets verses the individual assessed need)
– Health promotion model which is aimed at prevention
rather than cure
– Voice of the users: Support groups for those living with
cancer
– Further clinical trials and assessment of products
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Conclusion
Oral Mucositis is expected in 98% of our patient population, and remains a
very serious complication in head and neck cancer treatment.
Oral Mucositis has a profound effect on morbidity, compliance and
treatment outcomes.
It can significantly lead to post treatment oral complications that are
potentially life long (Haas and McBride 2011)
Health Care Professionals can make significant contributions to the
management of Oral Mucositis and Oral Complications by challenging
boundaries and care delivery.
With limitations comes creativity!
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