Cancer therapy induced Mucositis

1. Cancer therapy induced
Mucositis
- Dr Deepika Malik
-Resident Radiation Oncology

2. Introduction
• Oral Mucositis - inflammation of the mucous
membranes of the oral cavity and oropharynx
characterized by tissue erythema, edema, and
atrophy, often progressing to ulceration.
• The clinical significance of CT- and RT-related
mucositis as a dose-limiting and treatment-
limiting side effect is well appreciated.

3. Pathophysiology of Mucosal Injury
• mucosal injury and subsequent healing are
not limited to the epithelium alone but
involve all layers of the mucosa, including the
extracellular matrix.
• A five-stage process has been postulated to
explain the complex molecular, cellular, and
histologic events that are associated with
mucosal injury

4. Phases in the development of oral
mucositis.
(Adapted from Peterson DE: New strategies for management of oral mucositis in cancer patients. J Support Oncol 2006;4:9–13.)

5. • 1. Initiation of tissue injury: Radiation and/or chemotherapy induce cellular damage
resulting in death of the basal epithelial cells. The generation of reactive oxygen
species (free radicals) by radiation or chemotherapy is also believed to exert a role in
the initiation of mucosal injury. These small highly reactive molecules are byproducts
of oxygen metabolism and can cause significant cellular damage.
• 2. Upregulation of inflammation via generation of messenger signals: In addition to
• causing direct cell death, free radicals activate second messengers that transmit signals
• from receptors on the cellular surface to the inside of the cell. This leads to
• upregulation of pro-inflammatory cytokines, tissue injury and cell death.
• 3. Signaling and amplification: Upregulation of proinflammatory cytokines such as
• tumor necrosis factor- alpha (TNF-α), produced mainly by macrophages, causes
• injury to mucosal cells, and also activates molecular pathways that amplify mucosal
• injury.
• 4. Ulceration and inflammation: There is a significant inflammatory cell infiltrate
• associated with the mucosal ulcerations, based in part on metabolic byproducts of the
• colonizing oral microflora. Production of pro-inflammatory cytokines is also further
• upregulated due to this secondary infection
• 5. Healing: This phase is characterized by epithelial proliferation as well as cellular and
• tissue differentiation restoring the integrity of the epithelium.

6. Mucositis Assessment
• The WHO and NCI-CTC scales are the most
commonly used ones and combine
information from both the patient's signs and
symptoms and the patient's functional status
and ability to eat.

7. World Health Organization (WHO) scale for
oral mucositis
• Grade 0 = No oral mucositis
• Grade 1 = Erythema and Soreness
• Grade 2 = Ulcers, able to eat solids
• Grade 3 = Ulcers, requires liquid diet (due to
mucositis)
• Grade 4 = Ulcers, alimentation not possible
(due to mucositis)

8. National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) version 3.0
• Oral mucositis (clinical exam)
• Grade 1 = Erythema of the mucosa
• Grade 2 = Patchy ulcerations or
pseudomembranes
• Grade 3 = Confluent ulcerations or
pseudomembranes; bleeding with
minor trauma
• Grade 4 = Tissue necrosis;
significant spontaneous bleeding;
life-threatening consequences
• Grade 5 = Death
Oral mucositis
(functional/symptomatic)
Grade 1 = Minimal symptoms, normal
diet
Grade 2 = Symptomatic but can eat
and swallow modified diet
Grade 3 = Symptomatic and unable to
adequately aliment or hydrate orally
Grade 4 = Symptoms associated with
life-threatening consequences
Grade 5 = Death

9. Chemotherapy induced mucositis

10. Incidence and risk factors
• The type of chemotherapeutic agents that are
used, the specific dose, route, and frequency
of administration, and whether the
chemotherapy is given as monotherapy or in
combination with other agents and modalities
of treatment significantly affect the degree of
injury

11. Chemotherapy drugs more associated wth mucositis are
• Antimetabolites such as methotrexate and 5-FU
• Antitumor antibiotics such as doxorubicin,
• platinum agents such as cisplatin,
• purine analogs such as cytarabine, and
• topoisomerase inhibitors such as etoposide
-Methotrexate and etoposide are secreted into the saliva
thus enhancing mucosal toxicity.
- Irinotecan, although notorious for causing gastrointestinal
mucositis in the form of diarrhea, has limited oral toxicity

12. The time course of mucosal injury
• 5-FU-induced mucositis is usually first noticed 3
to 7 days after initiation of therapy. Incidence
peaks at 7 to 12 days and diminishes by around 2
to 3 weeks.
• Although there has long been the belief that
continuous administration of 5-FU carries a
higher risk of mucositis than does bolus
administration of 5-FU, a meta-analysis of trials
failed to support this association

13. • When chemotherapy is used in combination
with radiation therapy to treat cancer of the
head and neck, the rate of mucositis
approaches 90% to 100% of patients

14. • The role of age and gender in the
development of mucositis has not yet been
clearly defined.
• poor oral hygiene, dental caries, periodontal
disease, and high titers of herpes simplex virus
(HSV) and positive cultures for Candida
tropicalis are generally accepted to be risk
factors

15. • interpersonal variability in the development of
mucositis ,could be due to the differences in
metabolism of the chemotherapeutic drugs
from person to person.

16. Prevention of Chemotherapy-
Mucositis

17. • improved quality of life for patients receiving
chemotherapy
• reduction of the rate of life-threatening
infections that are thought to be originating
from the oral mucosa.
• improve the effectiveness of antineoplastic
therapy by preventing treatment
modifications during subsequent cycles and
permitting more dose-intensive therapies

18. Oral hygiene
• include oral cavity screening and dental
consultations;
• basic oral care with tooth brushing, flushing,
and rinsing;
• regular inspection of the oral cavity;
• and avoidance of substances such as smoking,
alcohol, and spices.

19. • During therapy, oral hygiene should be maintained with
rinses four to six times a day using either sterile water,
normal saline, or sodium bicarbonate solutions, and
patients should brush their teeth at least twice daily with a
soft or ultra-soft tooth brush or a toothette (i.e., foam swab
on a stick).
• Use of toothpaste is optional, and daily dental flossing
should be done only by patients who are experienced in
the technique, if it can be done without trauma.
• Orthodontic appliances and space maintainers can be
removed during therapy, although if good tissue integrity
and satisfactory daily oral hygiene are maintained, their use
can continue during the initial conditioning phase

20. Antimicrobial agents
• Microbes use the already damaged gastrointestinal mucosa as a
portal of entry, thus increasing the risk of infectious complications.
• Of all the antiseptics, chlorhexidine has been most extensively
studied in multiple randomized trials, and the results have been
mixed. Therefore, its regular use is not recommended.
• Isenagan, a naturally occurring peptide with a broad antimicrobial
spectrum, has also failed to show benefit.
• Although one small placebo-controlled randomized trial has shown
benefit for the prophylactic use of topical povidone-iodine, further
study is needed before this agent is accepted in clinical use.
• Regarding systemic antibacterial prophylaxis, data are also not
convincing, and systemic antimicrobials therefore are not
recommended at this time for the prevention of mucositis
• antifungal medications are currently not recommended for the
prophylaxis of oral candidiasis in patients receiving chemotherapy,

21. Cryotherapy
• 5FU based chemotherapy- cryotherapy works by causing
local vasoconstriction during periods of peak 5-FU blood
concentration, thus decreasing the delivery of 5-FU to
the oral mucosa.
• therapy is administered by having the patient suck on
crushed ice, starting 5 minutes prior to 5-FU
administration and continuing for a total of 30 minutes.
• A longer duration of oral cryotherapy (60 minutes) does
not appear to provide any additional benefit in this
setting
• Also used for edatrexate,melphalan

22. Antioxidants, Anticholinergics, and
Coating Agents
• insufficient evidence exists regarding the effectiveness of
antioxidant compounds such as tretinoin and vitamin E in
preventing oral mucositis in patients receiving chemotherapy.
• A small randomized trial of zinc sulfate reported a statistically
significant benefit in preventing severe mucositis; more
investigation is warranted before accepting this agent as standard
practice.
• There is also insufficient evidence to support the prophylactic use
of Propantheline, an anticholinergic drug that is thought to reduce
the amount of etoposide secreted in the saliva.
• Mixed data exist on the role of sucralfate, a coating agent;
therefore, sucralfate is not currently recommended for the
prevention of oral mucositis.

23. Anti-inflammatory Agents
• cytokine inhibitors and anti-inflammatory agents have
not yet proven to be efficacious.
• Pentoxifylline, a TNF-α and IL-2 inhibitor, is currently
not recommended in either the standard
chemotherapy or bone marrow transplant setting.
• Benzydamine mouthwash has been approved for
radiation-induced mucositis in Europe and Canada and
is currently being tested in the United States.However,
evidence regarding its use in prevention of
chemotherapy-induced mucositis is weak, and it is
currently not recommended in this setting.

24. Amino acids
• Multiple trials to date have attempted to investigate the beneficial
potential of different glutamine preparations through both the
parenteral and oral routes, with mixed results
• Saforis, an oral suspension form of L-glutamine with an enhanced
delivery system is being tested in breast breast cancer patients on
anthracycline-based regimen. Showed reducton in grade 2
mucositis incidence
• although glutamine is not yet officially recommended for the
prevention of chemotherapy-induced oral mucositis, results of
several studies are promising, and if subsequent data are
confirmatory, recommendations could change.
• The Food and Drug Administration (FDA) recently approved one
such preparation, palifermin, for use in preventing mucositis
induced by myeloablative chemotherapy

25. Growth factors
• Growth factors, systemically or topically, are
hypothesized to help prevent oral mucositis due
to their potential to improve healing.
• the data are inconclusive as yet (Cochrane).
• A recent meta-analysis found a benefit for
prophylactic treatment with systemic growth
factors but not for topical preparations.
• However, the results of the meta-analysis were
largely dependent on one strongly positive study
alone, and further evidence is needed

26. Low level laser therapy
• might promote healing and reduction of pain
in patients who are at risk for oral mucositis.
• Although no guidelines regarding its use exist
yet, further investigation encouraged.

27. Treatment of chemotherapy induced
mucositis
General recommendations that are frequently given
to the patients with established mucositis
• the avoidance of spicy, coarse, hot, cold, or acidic
foods or juices or medications or beverages
containing alcohol and the encouragement of
rather soft, moist foods and nonalcoholic
beverages.
• proper hydration, nutrition, infectious
surveillance, and psychological support, all of
which can significantly affect the patient's well-
being and quality of life.

28. mouthwashes
• For patients with established mucositis, one of the first
therapeutic measures that is frequently used consists of
having the patients rinse their mouths every 2 to 4 hours
with a solution of salt and baking soda (1/2 teaspoon salt
plus 1/2 teaspoon baking soda in an 8-ounce glass of warm
water).
• In one multicenter study, 200 patients receiving standard
chemotherapy, who followed a carefully planed oral
hygiene protocol (PRO-SELF), were randomized to one of
three different mouthwashes: salt and soda, chlorhexidine,
or “magic” mouthwash (lidocaine, Benadryl, and Maalox).
No significant differences were observed in time to
cessation of the signs and symptoms of mucositis among
the three regiments; salt and soda was the least costly

29. • Chlorhexidine mouthwashes are not
recommended, since studies have failed to
support the use of this agent for the
treatment of established mucositis.[
• Coating agents, such as sucralfate, have also
failed to show any benefit for the treatment of
established chemotherapy-induced mucositis
when tested in small randomized trials.

30. Antiinflammatory agents
• Anti-inflammatory agents have failed to find a
role in the treatment of chemotherapy-
induced mucositis.

31. Growth factors
• GM-CSF, systemically or topically as a
mouthwash, might stimulate proliferation of
endothelial cells and promote keratinocyte
growth, thus enhancing recovery of oral
mucositis.
• However, studies have been limited and are of
poor methodological quality

32. Systemic analgesics
• Oral mucositis pain can be severe and can
significantly interfere with the quality of life of
patients receiving chemotherapy.
• Management should follow the same
aggressive guidelines that are used to treat
pain in patients with cancer in general.

33. Summary of prevention of chemo
induced mucositis
• The importance of instituting oral hygiene protocols in patients receiving
chemotherapy is well established.
• Cryotherapy is the most conventional and easy-to-use preventive method,
at least for 5-FU-based bolus therapy, and appears to have implications for
other chemotherapeutic regimens as well, such as edatrexate and high-
dose melphalan therapy.
• The role of antibiotics, either topically or systemically, has not yet been
established.
• Glutamine supplementation in the form of AES-15 (Saforis) has recently
shown promise as a potentially effective agent.
• The FDA has approved palifermin, a keratinocyte growth factor
preparation, for use with high-dose chemotherapeutic regimens
associated with high rates of mucositis, and it has shown promise in other
settings as well.
• Low-level laser therapy has shown promise, but it is limited to centers that
are able to support its use.

34. Conclusion- t/t of chemo induced
mucositis
• There is overall lack of evidence regarding the efficacy of
various agents in promoting healing of the oral mucosa
after mucositis is established.
• Systemic analgesic therapy of mucositis pain with narcotic
medications is well established and recommended.
• Antibiotics and/or antifungal medications should be given
to patients who have evidence of infection.
• In the palliative setting, various mouthwashes are widely
used in clinical practice based on provider preference and
experience.
• Salt and baking soda mouth rinses appear to be the most
economical solution, although efficacy has not been clearly
established

35. Radiotherapy induced mucositis

36. Etiology
• Acute mucositis results from the loss of squamous epithelial cells
owing to the sterilization of mucosal stem cells and the inhibition of
transit cell proliferation. This leads to a gradual linear decrease in
epithelial cell numbers.
• As radiation therapy continues, a steady state between mucosal cell
killing and mucosal cell regeneration may occur because of an
increased cell production rate from the surviving cells.
• Usually, however, cell regeneration cannot keep up with cell killing,
and partial or complete denudation develops.
• This presents as patchy or confluent pseudomembranous mucositis.
• Healing eventually occurs when cells regenerate from the surviving
mucosal stem cells.
.

37. • The oral cavity mucosa, having a relatively high turnover rate,
change early during a course of fractionated external-beam
radiation therapy.
• With 200-cGy fractions per day, 5 days per week, mucosal erythema
is typically noted within the first week or two of treatment.
• By approximately 2 to 3 weeks, the erythematous mucosa develops
small whitish yellow patches called patchy pseudomembranous
mucositis.. This acute reaction is typically accompanied by oral
discomfort.
• In many patients, the patchy mucositis becomes confluent by the
third or fourth week of radiation therapy and can be associated
with significant pain

38. • The severity of mucositis is related to the daily dose of radiation therapy, the total
cumulative dose, the volume of irradiated tissue, and the use of concurrent
radiation-sensitizing and/or mucositis-inducing chemotherapeutic agents.
• At fractions of 170 to 180 cGy daily, 5 days per week, the maximal reaction is
typically intense erythema with occasional patchy mucositis.
• If the daily dose is increased to 200 cGy or more, as in the case of altered
fractionation schedules such as hyperfractionation (110 to 150 cGy twice a day) or
accelerated fractionation (160 cGy two or three times a day or concomitant boost
with 180 cGy in the morning and 150 cGy in the afternoon), and the treatment
volume is large (the entire oral cavity), cell killing will exceed the proliferative
capacity of the epithelial stem cells, and almost all patients will have confluent
mucositis by the third week of radiation therapy.
• In patients with metallic dental restorations, a prominent mucositis frequently
develops on the adjacent buccal mucosa and/or the lateral border of the adjacent
tongue or both as a result of backscattering of low-energy electrons.

39. • After external-beam radiation therapy, the mucous
membranes normally heal within 4 to 6 weeks,
although an occasional patient might require up to 12
weeks or even several months. The latter is particularly
true of patients treated with concurrent radiation-
sensitizing chemotherapy.
• The mucositis that is produced by an interstitial
radioactive implant typically appears 7 to 10 days after
removal and is maximal approximately 2 weeks after
removal.

40. Discontinuation of treatment due to
mucositis
• Radiation-induced oral mucositis can result in intense pain,
which may substantially limit adequate hydration and
nutrition, prevent proper oral hygiene, serve as a portal for
infection, and affect speech
• At times, the treatment might be discontinued altogether
before delivery of a potentially curative dose of radiation
therapy.
• Randomized clinical trials have demonstrated improved
local control and survival when altered fractionation
schemes that deliver conventional or higher doses of
radiation therapy are used over a shorter-than-
conventional period.
• Therefore, a break in radiation therapy because of
mucositis may lead to treatment failure.

41. Prevention and treatment of RT
mucositis
• Benzydamine hydrochloride 0.15% oral rinse, a
nonsteroidal drug, that has analgesic, anesthetic, anti-
inflammatory, and antimicrobial properties, is effective,
safe, and well tolerated for prophylactic treatment of
radiation-induced oral mucositis
• Trials do not provide convincing data of sufficient
clinical magnitude to recommend use of antimicrobial
mouthwashes (chlorhexidine or benzydamine),
antibiotic lozenges, or paste as part of standard
practice.

42. • Improved pain management in patients undergoing radiation therapy for
head and neck cancer with daily nursing intervention consisting of
instructions on the use of mouthwashes and a three-step analgesic
protocol consisting of acetaminophen, acetaminophen with codeine
suspension, and liquid morphine for relief of mild, moderate, and severe
pain, respectively.
• Many narcotic pain medications come in a liquid formulation that is
relatively easy to swallow or can be administered through a feeding tube.
• Fentanyl patches are also very effective for patients who cannot swallow.
• A topical morphine mouthwash might be a more effective treatment for
mucositis pain

43. • sucralfate suspension, an agent that appears to
provide a protective barrier and may also have a
cytoprotective effect. (The latter may be
mediated through prostaglandin release,
resulting in increased mucosal blood flow,
increased mucus production, increased mitotic
activity, and a surface migration of cells.)
• the randomized trials of sucralfate for therapy-
induced mucositis do not establish a role for
sucralfate in clinical practice.

44. • Painting the buccal mucosa with a 2% silver nitrate solution
for several days before radiation therapy stimulates normal
mucosa repopulation during radiation therapy, producing a
significantly less severe mucosal reaction and faster
mucosal healing after completion of radiation therapy.
•
• Low-energy laser therapy might also activate epithelial
healing.
• Zinc sulfate, α-tocopherol, and intravenous L-alanyl-L-
glutamine have been found to be effective in decreasing
the severity of radiation-induced mucositis and oral
discomfort in placebo-controlled prospective trials.

45. • Other preliminary studies have investigated
the direct application of a prostaglandin E2 gel,
the use of oral glutamine, and daily use of
subcutaneous GM-CSF.
• Results of pilot studies suggested that GM-
CSF might be quite effective in the prevention
and treatment of radiation-induced oral
mucositis

46. • A multicenter study of intravenous palifermin to
reduce mucositis in patients with head and neck cancer
receiving chemoradiotherapy is being conducted by
the Radiation Therapy Oncology Group.
• The radioprotector amifostine has been evaluated as a
means of preventing radiation-induced acute
mucositis. Nausea, vomiting, hypotension, and allergic
and injection site reactions are common side effects of
this drug. The questionable efficacy and significant
toxicity are associated with remarkably increased costs

47. • Sophisticated radiation therapy treatment planning limit the
volume of normal tissues that are irradiated and thereby reducing
the severity of normal tissue reactions.
• (computed tomography-based target delineation, intensity-
modulated radiation therapy and simple, custom-made, intraoral
devices that are designed to exclude uninvolved tissues from the
treatment portals or to provide shielding of tissues within the
treatment area.
• Patients with primary cancers of the oral cavity, oropharynx,
paranasal sinuses, and salivary glands are the best candidates for
the use of such devices.
• Packing gauze between metallic dental restorations and mucosa of
the lateral tongue and buccal area appears to be very beneficial in
minimizing the dose from scattered radiation.

48. Summary – RT induced mucositis
• Standard practice often includes aggressive, good oral hygiene consisting of
brushing teeth after each meal, using a soft toothbrush and baking soda
toothpaste, and rinsing the mouth every 2 hours throughout the day with salt and
baking soda
• Patients should be instructed to avoid the use of irritating or abrasive substances
such as commercial toothpastes and mouthwashes; tobacco; alcoholic beverages;
extremely hot or cold drinks or foods; very spicy foods; acidic foods such as citrus
fruits and their juices; and foods that are hard and coarse, such as pretzels, raw
vegetables, potato chips, crackers, and hard bread.
• When discomfort develops, topical anesthetic agents can be used.
• As the pain progresses, use of systemic analgesics, including acetaminophen with
codeine suspension might become necessary.
• The mucosa of patients undergoing radiation therapy to the oral cavity should be
examined at least once a week, and antibiotic or antifungal medications should be
prescribed as infections are documented.
• Clotrimazole troches, one dissolved in the mouth five times a day for 14 days,
generally work well for oral candidiasis. However, if significant mucositis, altered
taste, or xerostomia has developed, the troches might not be tolerated. In this
situation, nystatin oral suspension or fluconazole in tablet or liquid form is often
effective. Fluconazole is more effective than nystatin.

49. • Thankyou.

50. •
The Radiation Therapy Oncology Group (RTOG) has
developed the Acute Radiation Morbidity Scoring
Criteria for the evaluation of Radiotherapy treatments.
• The RTOG grading is reliant on a clinician's ability to
judge the anatomical changes associated with oral
mucositis (size and characteristics of ulceration).
•
•

51. RTOG Scoring Criteria for mucositis
• Grade Description
• 0 (none) No change over baseline
• I (mild) Irritation, may experience slight pain, not
requiring analgesic
• II (moderate) Patchy mucositis that may produce
inflammatory serosanguinitis discharge; may experience moderate
pain requiring analgesia
• III (severe) Confluent, fibrinous mucositis, may include
severe pain requiring narcotic
• IV (life-threatening) Ulceration, hemorrhage, or necrosis