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Oral Mucositis in Hematopoietic Stem Cell
Transplantation (HSCT): position statement
by Gruppo Italiano Trapianto di Midollo
Osseo (GITMO) Nurses Group
Stefano Botti1, Valentina De Cecco2, Letizia Galgano3, Gianpaolo Gargiulo4,
Antonio Magarò5, Laura Orlando6
Research Nurse, Hematology Unit, ASMN-IRCCS Reggio Emilia;
Nurse, Pediatric Onco-hematology Unit, Pol. S. Matteo, Pavia;
3
Nurse, Bone Marrow Transplant Unit, Careggi Hospital, Florence
4
Nurse, HSCT Unit, Federico II University Hospital, Naples;
5
Nurse,Onco-hematology Unit, European Institute of Oncology, Milan;
6
Head Nurse, Onco-hematology Unit, European Institute of Oncology, Milan. Head Nurse
GITMO NG
1
2
SUMMARY
Mucositis is a serious inflammatory complication affecting oral and gastro-intestinal mucosa of cancer patients undergoing chemotherapy and/or radiotherapy. It is one of the
most debilitating effects in patients receiving Hematopoietic Stem Cell Transplantation
resulting from harmful drugs used in conditioning regimens. Pathogenesis of mucositis
consists in some complex molecular modifications induced by chemotherapy and radiotherapy, with or without inflammation. Risk factors for the development of mucositis can
be related to the patient or treatments charateristics. Literature reviews indicate that a
more systematic approach based on feasibility, education and adherence to oral hygiene should be pursued and that hospitals and health care organizations should have
policies and specific set of protocols leading to an appropriate oral care. Guidelines
on oral assessment, support, care and documentation should be implemented in every
department and ward. The GITMO NG expert panel has wanted to develop a series of
evidence-based and expert opinon based suggestions on basic oral care. In the belief
that the main ways to find effective strategies and to develop new clinical research are
made up by health care professionals skills and training and a common approach to oral
care interventions.
Key words: oral mucositis, stomatitis,
bone marrow transplantation, stem cell
transplantation, neoplasms, conditioning regimens, oral care, chemotherapy,
prevention, treatment.
Correspondence:
Stefano Botti
Research Nurse, Hematology Unit,
ASMN-IRCCS Reggio Emilia
E-mail: [email protected]
◗◗◗ INTRODUCTION
This document aims to provide general
suggestions and recommendations for
the assessment, prevention and intervention on oral mucositis (OM) in patients who underwent transplantation
of hematopoietic stem cells (HSCT).
The pathophysiological mechanisms
of mucositis, with some exceptions,
must consider arguments common to
DECISIONS
MAKING
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S. Botti, et al.
the areas of chemotherapyadministration and radiation therapy, to avoid
an analysis focused only on patients
undergoing HSCT.
Any proposed solution cannot be separated from the context of treatment,
the type of pathology and the setting
of evidence and recommendations.
In June 2010 and January 2014, the
Italian Ministry of Health published
two Guidelines (GL) for the promotion
of oral health and prevention of oral
disease respectively in pediatric and
adult patients who have to undergo
chemotherapy and/or radiotherapy
(1, 2).
The purpose of these GL is to provide
“evidence-based”recommendations
and directions for the management of
problems involving the oral cavity, in
patients candidate to antineoplastic
treatment, during treatment or who
have completed it.
◗◗◗ BACKGROUND
Mucositis is a serious inflammatory
complication affecting oropharyngeal mucosa, esophagus and gastro
enteric (GE) tract, developed by cancer patients undergoing chemotherapy and/or radiotherapy.
Oral mucositis is found in 15-40% of
patients treated with conventional
chemotherapy, in 70-90% of patients
undergoing hematopoietic stem cell
transplantation (HSCT) with myeloablative conditioning (MAC) (3), in 80%
of patients receiving radiotherapy for
cancer of the head and neck (H&H),
with a percentage of hospitalization,
for the consequences related to mucositis, varying between 16% and 32%
(4).
Sixty percent of patients undergoing
HSCT with Total Body Irradiation (TBI)
and a variable percentage between
30% and 50% of patients undergoing
HSCT without TBI, develop severe (5)
mucositis (WHO 3-4) (6), with a devastating impact on quality of life. 60% of
patients receiving HSCT require additional treatment for the consequences of mucositis (7).
An observational study (8) conducted within the GITMO (Italian Group
for Bone Marrow Transplantation), on
1841 patients undergoing HSCT between 2002 and 2006, reveals a percentage of development of oral mucositis of 71%, with a percentage of
21.6% of severe mucositis lasting about
10-14 days.
Two studies (9, 10) reported data on
additional costs from $ 2,700 to $ 5,600,
depending on the severity, for each
patient who develops OM during a cycle of myelosuppressive chemotherapy and from $ 1,700 to $ 6,000, for a
patient who develops OM during chemo/radiotherapy for head and neck
malignancies.
Oral mucositis is one of the most debilitating effects in patients receiving
HSCT (11) and is the result of the epithelial and submucosal damage resulting from harmful drugs used in conditioning regimens (7).
Today we consider the pathogenesis
of mucositis as a complex processthat
is established as a result of complex
molecular modifications induced by
chemotherapy and radiotherapy,
with or without inflammation (12).
The recent abandonment of the historical paradigm of cell death, as
the main cause of mucosal lesions, in
pathobiological vision of the impact
of chemoradiation on mucosal cells,
has led to a better defining the patho-
Oral Mucositis in Hematopoietic Stem Cell Transplantation (HSCT)
physiology of mucositis. Therefore,
there are a few treatment options,
since recognition of biological complexity has allowed the development
of a number of treatment options that
are currently being studied (13).
Pathophysiology or Pathobiology?
The previous pathophysiological 4
stages model (14) (Figure 1) in which
a Vascular phase (1st-3rd days), an
Epithelial phase (4th-5th days), an Ulcerative phase (6th-12th days), an
Healing phase (after 12 days) were
recognizable has been reconsidered
by the same author and replaced by
a pathobiological 5 phase model (15)
(Figure 1): Beginning, Iper-regulation
and Message Generation, Signal Amplification, Ulceration, Healing (Figure
2, Table 1).
Risk factors for the development of
mucositis can be related to the patient: previous condition of the oral
cavity, lifestyle (smoking and alcohol),
oral hygiene habits, age (most severe
in children and in the elderly), gender
(higher incidence in women), individual susceptibility,nutritional status.
But most can be associated with the
treatment: type of drugs used (methotrexate, etoposide and radiotherapy increase its frequency), the doses
(MAC or RIC), the combination of antineoplastic drugs, the level of myelosuppression reached, the reduced
secretion of IgA, the development of
bacterial, viral or fungal infections, the
use of drugs that can cause dryness
(antiemetics, opiates, drugs), acute or
chronic GvHD.
Table 2 shows the main conditioning
regimens responsible for severe mucositis (16).
Moreover mucositis can be aggravated by factors such as diabetes,
rheumatic diseases, traumatic ulcers
caused by or dentures and orthodon-
FIGURE 1 • Oral Mucositis pathophysiology. Reproduced from Sonis et al. [12]
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S. Botti, et al.
FIGURE 2 • Oral Mucositis pathobiology. Reproduced from Sonis et al. [12]
TABLE 1 • OM phases.
The phases of oral mucositis (Adapted from Sonis ST, 2009)
1
Initiation
•
•
•
•
•
-
The initial phase of the tissue damage is established shortly after administration of
radiotherapy or chemotherapy.
Radiotherapy and chemotherapy damage is beginning to damage to DNA.
The rupture of DNA strands involves tissue damage directly charged to the basal
epithelial cells and in the submucosa.
At the same time, generate Reactive Oxygen Species (ROS) that are crucial mediators of biological events downstream.
The outcome of the initial phase of mucositis include:
Formation of intracellular ROS.
Direct dependents of cells, tissues and blood vessels.
Beginning of other biological events.
Oral Mucositis in Hematopoietic Stem Cell Transplantation (HSCT)
2
Upregulation and
Message
Generation
•
•
•
•
3
Signal
•
Amplification
•
•
•
-
4
Ulceration
•
•
•
•
•
•
•
-
5
Healing
•
•
•
•
•
•
-
Various pathways that stimulate transcription factors are activated in response to
radiation, chemotherapy and ROS.
During the lipid peroxidation are released molecules bound to cell membranes,
resulting in induction of genes in immediate response.
All these changes occur not only the epithelium, but in all cells and layers of mucosa.
The phase of mucositis characterized by the induction and the generation of
messengers involves the induction of cell death clonogene, apoptosis and tissue
damage.
Proinflammatory cytokines damage the fabric and establish a positive feedback
circuit (positive feedback) that amplifies the primary damage caused by radiotherapy or chemotherapy started.
Note that, in the biological chaos accompanying the initial stages of mucositis,
the clinical picture is quiescent.
Although during these stages there may be a certain erythema of the mucous
membranes, tissues are mostly intact, and the patients have few symptoms. The
situation changes with the development of ulcers.
The results of the phase of signaling and amplification of mucositis are the following:
The harmful events focus on the epithelium and submucosal baseline.
Alteration of the environment generalized mucosal.
Alteration of the biological characteristics of the tissue, although the appearance
may remain normal.
The stage of ulceration of mucositis is the most significant for both patients and
caregivers.
The loss of the integrity of the mucosa leads to the development of extremely
painful lesions likely to surface colonization.
In neutropenic patients, the interruption of the mucosa serve as access routes for
microorganisms and often leads to bacteremia and sepsis.
Moreover, the products of the bacterial cell wall can penetrate the submucosa,
where they stimulate infiltrating monocytes to produce and release other proinflammatory cytokines.
Probably this promotes the expression of proapoptotic genes and enhances tissue damage.
The inflammatory cells then migrate to the base of the lesion for chemotaxis,
where they produce enzymes with detrimental action on the tissues.
The results of the phase of ulceration of mucositis are:
Amplification of cytokine
Inflammation
Pain
Risk of bacteremia and / or sepsis.
The phase of healing of mucositis starts with a signal from the extracellular matrix.
This leads to a recovery of epithelial proliferation and differentiation and to recover the local microbial flora.
After the healing phase the oral mucosa has a normal appearance; However,
despite the normal appearance, the environment of the mucosa has undergone
significant changes.
There is residual angiogenesis.
The patient is at increased risk of future episodes of oral mucositis and related
complications with subsequent anticancer therapy.
The results of the healing phase of mucositis are:
Intact epithelium
Look normal tissue
Residual angiogenesis
Increased risk of other episodes of mucositis.
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TABLE 2 • Conditioning regimens.
Regimen
No. of
studies
No. of
patients
Risk of Grade 3-4
oral mucositis
%
95% CI
Adult BMT
With TBI
8
611
64
61-68
Busulfan conditioning regimen (no TBI)
10
360
52
47-55
Other conditioning regimens (no TBI)
3
439
31
27-35
Stem cells: Myeloma
5
139
36
30-43
Stem cells: Solid tumors
9
266
27
24-31
7
320
42
37-47
3
36
27
13-42
4
59
31
25-40
Ara-C, idarubicin, fludarabine
4
192
20
10-33
Methotrexate
3
132
23
16-30
Mitoxantrone
1
66
12
5-21
Thiotepa/cyclophosphamide
1
51
6
1-14
Ifosfamide/etoposide
1
60
20
12-30
Pediatric BMT
With TBI
With busulfan/etoposide/cyclophosphamide
conditioning (no TBI)
With melphalan/carboplatin/etoposide
conditioning (no TBI)
Other pediatric regimens
tic appliances, the decay of the general conditions, the habit to assume
very hot, very cold, spicy or acidic
food. Inflammation of the oral cavity is manifested initially with mucosal
erythema and burning sensation and
later with ulcerations. Subjectively,
patients complain of very severe pain
with inability to eat, drink, swallow and
even speak.
The mucosal toxicity produced by
chemotherapy can be: direct, if
caused by cytotoxic chemotherapy
and radiotherapy; or indirect, if resulting from the action of systemic immunosuppression.
The consequences of this degenerative process are mainly related to an
increased risk of infections, to nutrition-
al problems like anorexia, to intense
pain, to a delay in recovery and consequent increase of inpatient-days, to
an increase in costs. The rate of mortality from infections related to oral
mucositis varies between 6 and 30%
(17).
About 38% of adult cancer patients
had symptoms of depression related
to the experience of oral mucositis
(18), some studies have shown a significant increase in mood disorders (19),
anxiety and depression (20) in patients
with severe mucositis.
We have analyzed the experience of
adult patients from the point of view of
their thoughts, feelings and concerns,
making an essential contribution to
the vision of a multidisciplinary ap-
Oral Mucositis in Hematopoietic Stem Cell Transplantation (HSCT)
proach to the problem and coming to
the conclusion that oral mucositis is experienced as a total negative experience and goes far beyond the simple
mouth pain, so the main theme that
emerges from the study is the patient’s
constant questioning about the usefulness of treatment (21).
Mucosa main disorders
• Blanching: caused by the initial vasoconstriction with capillary obliteration.
• Erythema: mucosal redness, is linked
to increased vascular permeability,
resulting in tissue edema and thinning of the mucosa.
• Mucosal atrophy and disepithelization: drastic reduction or disappearance of the epithelium surface.
• Ulcers: plans to pathogenic microorganisms (bacteria, fungi, viruses).
• Plaques: constituted by a fibrous
exudate which forms a pseudomembrane that is established on a
ulcerated edematous mucosa.
• Membranes: yellowish-white formations adherent to the ulcerated mucosa due to the presence
of keratin and a dense lamina rich
in collagen, tend to cracking and
bleeding.
• Injuries from Candida: manifests
with pseudo-membranes or punctate lesions that appear as white
patches on the tongue and mucous membranes.
• Herpetic lesions: manifest with painful vesicles which while breaking
result in scabs, sores frequently concern the district.
• Hemorrhagic gengivitis and gengival hypertrophy.
• Petechiae and submucosal hematoma.
• Lichen: mucosal hypertrophy of viral and/or autoimmune, frequent
manifestation in GVHD.
Signs and Symptoms
• Pain can be either marked as
“deep”, “burning”, “strong”, often
requires opioid therapy.
• Feeding difficulties: the patient
cannot swallow because of pain or
can have difficulties in chewing because of edema.
• Drooling: saliva loses its moisturizing, humectant and protective
functions, with overproduction of a
sticky,dense, liquid that the patient
struggles to expel and swallow.
• Xerostomia: massive reduction in
saliva production.
• Mucosal bleeding: may be spontaneous for the presence of extensive
ulceration or massive disepithelization, favored by thrombocytopenia.
• Dysgeusia: altered taste perception.
• Difficulty in articulating words.
Prevailing Zone
Generally the most affected areas
are:
• Lips
• Soft palate
• Hard palate
• Tongue
• Floor of the mouth
• Gums.
◗◗◗ ASSESSMENT
Regarding the assessment, in the last
30 years we have seen a variety of
rating scales proposed in the literature
with which health professionals can
“measure” the extent of the problem.
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All the tools must have the characteristics of “Validity” (ability to measure
the phenomenon for which they were
created) and “Reproducibility” (ability
to assess the phenomenon in different
contexts).The most used scales assign
a numeral score based on the severity
of specific signs or symptoms, are easy
to use, have a strong propensity to objectivity and reproducibility. There are
also “descriptive” types of scales that,
while describing the problem better,
are less comparable, require “expertise” and more training programs to
ensure a certain reproducibility in collection data.
Also there are “mixed” scales, where a
descriptive approach is accompanied
by a numerical score overall. In addition to use validated tools, a pre-transplant formal assessment should be defined, based on personal evaluation,
FIGURE 3 • Risk assessment.
TABLE 3 • WHO grading.
World Healt
Organization GRADING
Description
0
1
No Symptom
Irritation (mild discomfort) + / - erythema, no ulceration
2
Erythema, ulcers, can swallow solid
3
Erythema, ulcers, only liquid diet (solid diet not possible)
4
Mucositis extended, alimentation is not possible (liquid and solid)
Oral Mucositis in Hematopoietic Stem Cell Transplantation (HSCT)
anamnesis and clinical evaluation,
with the aim to define pre-treatment
risk level for development of oral complications (Figure 3).
The World Health Organization (WHO)
(6) has developed in the late ’70s a
rating scale (Table 3), which today is
still the most widely used worldwide for
its simplicity, validity and reproducibility in multiple contexts. It is characterized by the attribution of a score number ranging from 0 to 4 on the basis
of objective measurements, as the
redness and the presence of mucosal
ulcerations, and functional elements
(ability to eat solid foods and liquids).
The National Cancer Institute (NCI)
(22) has developed from a single matrix (CTC: Common Toxicity Criteria),
three different scales according to the
areas of use (conventional chemotherapy, radiation therapy, stem cell
transplantation).
The numerical scale NCI-CTC radiotherapy is based entirely on objective
findings such as erythema, presence
and extent of pseudomembrane, ulcers and necrosis; while, those referring to stem cell transplant and chemotherapy, include items such as difficulty in swallowing, and the use of
artificial nutrition. Some nursing groups
have developed scoring systems that
combine the evaluation of mucositis
with the patient care management,
producing scales with olistic connotation, including factors not necessarily
related to mucositis.
These are the rating scales of Tardieu
et al. (23), of Eilers et al. (24) (Oral
Assessment Guide) and the Western
Consortium for Cancer Nursing Research (WCCNR) (25), which include
functional and descriptive findings as
voice quality, the type of food eat-
en, swallowing, sores and dry mucous
membranes, infection, bleeding, and
the degree of hygiene and cleanliness.
In the past, other groups (26, 27) have
tried to develop tools with a strong research, based on individual aspects of
the problem and on systems of “items”
objectified as much as possible in an
attempt to eliminate the matter of
subjectivity, but the results have not
always been encouraging from the
point of view of applicability in the
contexts of care.
One, for example, is the case of the
Oral Mucositis Assessment Scale
(OMAS) (28) that has been tested by
multidisciplinary expert groups, separating the objective elements or primary indicators (erythema, ulcers)
from subjective or secondary indicators (pain, ability to take food, swallowing), this is unable to provide a unique
final score that represents the problem
in its entirety. Table 4 summarizes/compares the main evaluation instruments
of mucositis (29).
Prevention and Treatment
Given the significant economic and
social impact of the phenomenon, it
is at least strange that today, in addition to the substantial lack of viable
options and preventive treatment,
mucositis continues to have little “appeal” for clinicians and researchers all
around the world.
For this reasons there are still no guidelines for the approach to prevention
and treatment of mucositis supported
by a strong evidence-based effectiveness (30).
Also available are a very broad range
of options, on the basis of suggestions,
that are often poorly supported by
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TABLE 4 • OM assessment scales.
Scales used to assess oral mucositis
Source
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
WHO
No
changes
Pain,
erythema
Erythema, ulcers, can
eat solids
Only ulcers, liquid
diet
Impossible
alimentation
WCCNR
No
changes
Mild erythema,
1-4 ulcers,
mucosal moist,
no bleeding or
infection, mild
edema, avoid
hard foods,
hot or spicy
due to oral
sensitivity slight
discomfort
or burning
sensation
Moderate erythema,
>4 lesions that are
not coalescing,
mucosal bleeding
Poll, xerostomia mild,
moderate edema,
evidence of mild
infection, able to drink
liquids and eat light
food soft, continuous
pain with moderate
analgesic use
intermittent
Severe erythema,
>1 ulcer confluent,
spontaneous
bleeding,
xerostomia marked,
severe edema,
infections, feeding
impossible, severe
pain that requires
constant systemic
analgesics
N/A
NCI CTC
(HSCT)
No
changes
Painless ulcer
or mild pain
without injury
Painful erythema,
edema or ulcers,
but can swallow
Painful erythema,
edema or ulcers
preventing
swallowing or
requiring hydration
or nutritional support
Severe
ulceration
requiring
prophylactic
intubation or
resulting in
documented
aspiration
pneumonia
NCI CTC v.2
(radio)
No
changes
Erythema
Moderate
pseudomembranous
reaction (patches
generally ≤1.5 cm in
diameter)
Confluent
Necrosis
pseudomembranous or deep
ulceration
reaction (≥ 1.5 cm
in diameter)
NCI CTC
(chemo)
No
changes
Painless ulcers, Painful erythema,
edema or ulcers, but
erythema, or
can eat or swallow
mild soreness
in the absence
of injury
Painful erythema,
edema or ulcers
requiring IV
hydration
Severe
ulceration
or requires
parenteral
or enteral
nutritional
support or
prophylactic
intubation
Oral
Mucositis
Assessment
Scale
(OMAS)
ulceration
(28)
Normal
Less than 1 cm
square
Between 1-3 cm
squares
Greater than 3 cm
squares
N/A
OMAS
Erythema
(28)
Normal
Not serious
Serious
N/A
N/A
Oral Mucositis in Hematopoietic Stem Cell Transplantation (HSCT)
TABLE 5 • Chochrane reviews evidences.
Prevention
Intervention
Source
Strength of Evidence
Cryotherapy
Cochrane rev. 2013
Some evidence
Keratinocyte Growth Factor (KGF)
Cochrane rev. 2013
Some evidence
Aloe Vera
Cochrane rev. 2013
Weak evidence
Amifostine
Cochrane rev. 2013
Weak evidence
Intravenous glutamine
Cochrane rev. 2013
Weak evidence
GCSF subcutaneously
Cochrane rev. 2013
Weak evidence
Honey
Cochrane rev. 2013
Weak evidence
Low levels laser therapy (LLLT)
Cochrane rev. 2013
Weak evidence
Polymixin Trombamicin Anfhotericin (PTA)
Cochrane rev. 2013
Weak evidence
Sucralfate
Cochrane rev. 2013
Weak evidence
Chlorhexidine
Cochrane rev. 2013
NO evidence
Cochrane rev. 2010
Limited evidence
Treatment
LLLT
actual evidence of efficacy. Clearly,
for the construction of their own protocol of mucositis management, centers always have relied much more on
the experience gained in the field by
practice of involved health professionals than on the scientific evidence actually available.
Literature reviews indicate that a more
systematic approach to the care of
oral hygiene should be pursued, but
also that the way to go, in the establishment of protocols for mucositis prevention and treatment, does not lie
in the identification of specific treatment agents but rather in a shared
approach focused on the feasibility,
adherence and patient education.
The presence of oral hygiene protocols developed by multidisciplinary
teams can reduce the severity of mucositis and should include an educa-
tional component directed to the patient and to the operators (5).
Dental treatment is necessary before
starting cancer therapy, an important factor for all patients, although in
some cases it is notfeasible in relation
to patients clinical conditions.
Other factors to be taken into consideration during treatment are the
frequent and systematic observation
and the assessment of pain control.
The frequent assessment of the state
of the oral cavity can be achieved
either by the patient, using validated instruments, by medical personnel
with the tools that we discussed in the
previous paragraph. The GITMO NG
produced this document analyzing
the guidelines of the Italian Ministry of
Health (1, 2), on the basis of the main
international Guidelines (5, 31, 32) and
literature Reviews (30, 33).
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S. Botti, et al.
FIGURE 4 • MASCC-ISOO level of evidence and strenght of recommendations.
They took into account aspects of
nursing competence and divided the
recommendations according to the
strength of the benefit.
Always bearing in mind that all interventions have been studied only in relation to certain groups of patients undergoing specific treatment regimens,
the generalization of the results to other forms of cancer and other types of
treatment should be considered with
caution because some benefits can
be specific only for certain types of
cancer or certain types of treatment
(32).
Table 5 summarizes the main evidence
in Cochrane reviews for prevention
and treatment.
Figure 4 summarizes Multinational Association of Supportive Care in Cancer-International Society of Oral Oncology (MASCC/ISOO) level of evidence, grade of recommendation
and guideline hierarchy. Table 6 summarize the MASCC-ISOO recommendations (Table 6).
◗◗◗ TIPS FOR PRACTICE
Besides the recommendations and
suggestions of the literature, this document wants to provide a set of Recommendations for daily practice that are
the result of a broad sharing among
experts within the GITMO NG. The basic belief is that, although the attempt
Oral Mucositis in Hematopoietic Stem Cell Transplantation (HSCT)
TABLE 6 • Multinational Association of Supportive Care in Cancer-International Society of Oral
Oncology (MASCC-ISOO) recommendations.
Object
Level of Evidence
and Strength of
Recommendation
Source
General (applicable to HSCT-hematopoietic stem cell transplantation) - Prevention
Development of protocols for oral hygiene for the prevention of oral III
mucositis (OM) that include patient education and worker training III B
MASCC / ISOO 2014
MASCC 2004
Iseganan rinses MUST NOT be used to prevent OM
II
MASCC / ISOO 2014
Sucralfate mouthwash MUST NOT be used for the prevention of OM I
in patients undergoing chemotherapy or radiation therapy
MASCC / ISOO 2014
General (applicable to HSCT) - Treatment
Rinse with a solution of Doxepin 0.5% for the treatment of pain
IV
MASCC / ISOO 2014
Sucralfate mouthwash MUST NOT be used for the treatment of OM in I
patients undergoing chemotherapy or radiation therapy
MASCC / ISOO 2014
Transdermal fentanyl for the treatment of pain in patients undergo- III
ing conventional chemotherapy or high-dose, with or without Total
Body Irradiation (TBI).
MASCC / ISOO 2014
Chlorhexidine rinses MUST NOT be used for the treatment of mucositis III C
MASCC 2004
HSCT - Prevention
KGF-1 (palifermin) for the prevention of OM in hematolog- II
ic patients undergoing autologous HSCT with myeloablative I A
conditioning (MAC) and TBI
MASCC / ISOO 2014
MASCC / ISOO 2007
Low Level Laser Therapy (LLLT) for the prevention of OM in patients II
undergoing HSCT with MAC, with or without TBI
II B
MASCC / ISOO 2014
MASCC 2004
Oral or cryotherapy for the prevention of OM in patients undergoing III
HSCT receiving High-Dose Melphalan, with or without TBI
II A
MASCC / ISOO 2014
MASCC / ISOO 2007
Glutamine intravenous MUST NOT be used for the prevention of OM II
in patients undergoing HSCT with MAC, with or without TBI
II B
MASCC / ISOO 2014
MASCC 2004
GM-CSF mouthwashes SHOULD NOT be used for the prevention of II
OM in patients undergoing HSCT with MAC
II C
MASCC / ISOO 2014
MASCC / ISOO 2007
Pentoxifylline orally SHOULD NOT be used for the prevention of OM in III
patients undergoing HSCT
II B
MASCC / ISOO 2014
MASCC 2004
Iseganan rinses MUST NOT be used to prevent OM in patients under- II
going HSCT with MAC, with or without TBI
MASCC / ISOO 2014
Pilocarpine orally SHOULD NOT be used for the prevention of OM in II
patients undergoing HSCT
MASCC / ISOO 2014
HSCT - Treatment
PCA (Patient Controlled Analgesia) with morphine for the treatment II
of pain from OM in patients undergoing HSCT
IA
MASCC / ISOO 2014
MASCC 2004
Others - Prevention
30 minutes of oral cryotherapy for the prevention of OM in patients II
receiving bolus 5-FU
MASCC / ISOO 2014
Benzydamine hydrochloride in mouthwashes for the prevention of OM I
in patients undergoing therapy for RX H&N (head and neck) Cancer
MASCC / ISOO 2014
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S. Botti, et al.
LLLT for the prevention of OM in patients undergoing RX therapy III
without concomitant chemotherapy for H & N Cancer
MASCC / ISOO 2014
PTA (polymyxin, tobramycin, amphotericin B) lozenges or tablets II
SHOULD NOT be used for the prevention of OM in H & N Cancer
patients receiving therapy RX
MASCC / ISOO 2014
Chlorhexidine rinses SHOULD NOT be used in the prevention of OM in III
H & N Cancer patients receiving therapy RX
MASCC / ISOO 2014
Pilocarpine orally SHOULD NOT be used for the prevention of OM in III
patients receiving H & N Cancer Therapy RX
MASCC / ISOO 2014
20-30 minutes of oral cryotherapy for the prevention of OM in pa- IV B
tients receiving bolus edatrexate
MASCC / ISOO 2007
Acyclovir MUST NOT be used to prevent OM
MASCC 2004
II B
Others - Treatment
Morphine rinses to 2% for the treatment of pain from OM in patients III
subjected to H & N RX therapy
Sucralfate MUST NOT be used for the treatment of OM in patients IIA
undergoing therapy for RX H & N Cancer
MASCC / ISOO 2014
MASCC / ISOO 2007
TABLE 7 • Tips for practice.
Aim
Action
Benefit
Education/
Information
of the patient
and his/her
family
Interview pre HSCT on the theme of mucositis
Counseling interventions before, during and after hospitalization processing and use of info-educational written material
Makes the patient informed of the possible
risks and benefits
Modification misconducts
Enhances alertness
Training
Continuing education of health professionals
Organization and participation to specific training events
Improve knowledge of the operators
Stimulates attention to the problem
Assessment
Assess the degree of mucositis every day and every time Allows scoring of mucositis
needed using a validated scale (preferably WHO)
Allows to identify signs and symptoms
Allows early initiation of strategies of “care”
Basic oral
hygiene
Writing, sharing, implementation, upgrade of specific pro- Health maintenance, integrity and function
tocols
of the mucosa
Sharing with the patient and his family
Reducing the risk of infection
Education
Uniformity of behavior
Oral hygiene several times a day, especially after all meals
Reducing the risk of infection
Using soft brush or very soft (in relation to pancytopenia) Reduces bacterial load
and non-irritating or abrasive toothpaste and flavor toler- It does not cause injury
ated
It does not cause bleeding
Removes residual organic material, food
and plaque
Using prepared fluorinated
Prevents tooth decay in pediatric patients
Rinse, often moisten the mouth with water
Keeps the mucosa moist and hydrated
It favors the elimination of residues
Lip care with creams or sticks softeners
Prevents dryness
Prevents injury
Oral Mucositis in Hematopoietic Stem Cell Transplantation (HSCT)
Dental
Supply
Nutrition
Hydration
Pain
Visit pre hospitalization and treatment
Avoid infectious outbreaks
Dental prophylaxis
Revision removable dentures
Reduces the risk of oral complications
Counseling during hospitalization
Multidisciplinary approach
Provides guidance on how to deal with mucositis
Avoid foods that are too hot, salty, spicy, fatty, irritating, Avoid injury to the mucosa
abrasive
Monitoring nutritional status
Maintenance of mucosal integrity
Strengthen calorie intake
Avoid malnutrition
Fractionate meals
Use Oral Nutritional Supplements (ONS) or Artificial Nutrition
(AN) according to cases
Maintain adequate hydration
Water balance (if necessary)
Prevents dryness
Prevents injury
Use of the saliva substitute several times a day
Improves xerostomia
Assess pain whenever necessary using a validated scale It allows to identify strategies for treatment
(eg. NRS)
Allows comparison with other
Systemic therapy of pain according to Guidelines: acet- Decreases discomfort
aminophen, tramadol, fentanyl, opiates according to the Decreases anxiety
intensity of mucositis
Improves QoL
Possible use of topical solutions (lidocaine)
Vomiting
Attention to the use of topical antifungal and mouthwashes Can prevent worsening of mucositis
that can stimulate a vomiting consequently worsen mucositis
Rinse your mouth after each episode of vomiting
Possible use of dilute solutions of NaHCO 3
Prevention
Can assist the systemic therapy and help
lessen the discomfort
Reduces acidity
Reduces microbial load
Stabilizes ph
Anti fungal topical: use products completely or partially ab- Prevent fungal infections
sorbed from the GI tract, the use of non-absorbable products (eg. Nystatin) has shown no evidence
Using mouthwashes in pre treatment in patients with prob- Reduces microbial load
lems inflammatory, infectious or poor oral hygiene
Possible use of mouthwashes spirits (if tolerated) until you Reduces microbial transiently
see the slightest sign of mucositis
Treatment
Products barrier
They can protect the mucosa from external
agents and minor injuries
Anti fungal systemic
Prevents fungal infections
Suspend any mouthwashes spirits at the slightest sign of Prevents irritation
mucositis preferring non-alcoholic solutions or saline (eg. Prevents pain
Saline)
Hydrates
Promotes healing of ulcers
Acyclovir cream herpetic lesions on the lips
Promotes healing of Herpes Labialis
219
220
S. Botti, et al.
to find new therapeutic solutions to
the problem is still a road to be pursued, present knowledge suggest that
attention must stay focused on sharing
and integration of multidisciplinary approaches, with developing pathways
and protocols centered on awareness
raising, training, education of health
professionals and their patients.
As written below (Table 7) responds
to the principles of Evidence Based
spread of behaviors, in which clinical
care decisions are the result of the interpretation and mediation between
various needs such as the presence or
absence of scientific evidences, the
preferences and the patient’s condition, the expertise of professionals,
and the available resources.
A special mention regards the wide
use of Nystatin to prevent local (oral)
fungal infections, even systemic.
The world’s most authoritative authors
argue the uselessness of this drug both
in the preventive phase of mycoses of
the oral cavity, and especially in the
treatment phase.
The Cochrane Review even makes
specific references to the futility of the
drug, the evidence supporting instead
the use of antifungals that are totally
or partially absorbed from the gastro
enteric tract.
To this end, our research group wants
to stimulate reflection on other aspects: as many other antifungal oral
liquid formulations, Nystatin is not tolerated because of its flavor and texture, and its use in patients with major
problems of nausea and vomiting, like
onco-hematological patients and patients undergoing HSCT, can only lead
to a worsening of emesis.
If we consider that vomiting, as amply
demonstrated in the literature, is one
of the main factors that predispose to
the development of mucositis and its
increased, we can reasonably doubt
the usefulness of the administration of
Nystatin in this setting.
Also do not forget that, and this is an
everyday experience common to all
operators of Hematology and Transplantation Program, the patient with
nausea, vomiting, mucositis, hardly
adheres to therapy with oral antifungals in syrup, to the possible development of resistance and non-adequacy of therapy.
On the last of these considerations,
but especially of the clear literature
indications, the GITMO Research Nursing Group, does not recommend the
use of Nystatin in the prevention and
treatment of mucositis in patients hospitalized in Transplant Program.
Further suggestions for
Oral Careby the Group
The working group has developed a
simple management protocol for basic oral care based on the expert opinion of the group members.
It is composed by three domains and it
is applicable in all care settings.
Hygene interventions:
• All patients who underwent HSCT
should be encouraged to maintain a good oral hygiene: brushing teeth gently at least twice a
day and after each meal with a
soft-bristle toothbrush and fluoride
toothpaste.
• Frequent change of toothbrush:
during pancytopenia the use of disposable soft toothbrushes is recommended.
• The brushes shall not be kept in disinfectant solutions.
• Consider the use of pediatric tooth-
Oral Mucositis in Hematopoietic Stem Cell Transplantation (HSCT)
•
•
•
•
•
paste if your normal toothpaste is
not tolerated.
Remove the toothpaste and rinse
thoroughly with water.
Mouthwashes are generally not required.
Dental floss or toothpicks should not
be used during pancytopenia.
Dentures should be worn as short as
possible, thoroughly cleaned after
each meal and left in specific solutions for dentures at night.
If patients are not autonomous in
oral hygiene a adequately trained
nurse or care givers CG should assist.
Early treatment of dryness:
• Ointment or cocoa butter for the
lips.
• Encourage oral hydration by drinking water.
• Frequent rinses with saline.
• Spittle substitutes or artificial lubricants in severe cases.
• Ice chips if they don’t causes discomfort.
• Chewing sugarfree gum or sucking pieces of fruit e.g. pineapple or
lemon.
• Ensure the removal of thick secretions by aerosol or with rinse solutions, with saline or bicarbonate
solution.
Gastro-Intestinal care:
• Preventing and treating emesis.
• Nutritional assessment may be useful in preventing exacerbations of
early OM and in case of high risk of
severe OM.
• Address the causes of altered taste
while encouraging the maintenance of oral intake of food and
water.
• Encourage the patient to maintain
a balanced diet.
Monitor oral intake of food and water.
• Avoid spicy food, highly acidic or
too hot, abrasive or crisp; pay attention to food that can damage
the mucosal surfaces.
• Avoid alcohol and tobacco.
Aknowledgements: Authors wish to
thank the Gruppo Italiano Trapianto di
Midollo Osseo e Terapia Cellulare (GITMO) in particular the Nurses Group.
Authors would also like to thank Dr.
Francesco Merli, Arcispedale S. Maria
Hematology Director and Dr. Alessia
Ruffini for support, editing and linguistic revision.
Conflict of interests: Authors declares
no conflict of interests.
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