31ENERO - JUNIO 2019 ODONTOLOGÍA VITAL

Evaluación longitudinal de la mucositis

oral en el trasplante de células madre

hematopoyéticas: un estudio piloto

Evaluación longitudinal de la mucositis

oral en el trasplante de células madre

hematopoyéticas: un estudio piloto

Longitudinal evaluation of oral mucositis in

hematopoietic stem cell transplantation: a pilot study

Longitudinal evaluation of oral mucositis in

hematopoietic stem cell transplantation: a pilot study

Carolina Eurich Mazur, Federal University of Parana, Brasil, carolmazur6@hotmail.com

Camila Pinheiro Furquim, Federal University of Parana, Brasil, camilapfurquim@yahoo.com.br

Samir Kanaan Nabhan, Federal University of Parana, Brasil, samir.nabhan@hc.ufpr.br

Geisla Mary Silva Soares, Federal University of Parana, Brasil, geisla.soares@ufpr.br

José Miguel Amenábar, Federal University of Parana, Brasil, jamenaba@ufpr.br

Cassius Carvalho Torres-Pereira, Federal University of Parana, Brasil, cassius.torres@ufpr.br

RE SU MEN

Objetivo: describir la incidencia y el puntaje de la mucositis oral (MO) y las morbilidades relacionadas

en individuos sometidos a trasplante de células madre hematopoyéticas (TCMH) a lo largo del período de

inmunosupresión. Métodos: Los sujetos con enfermedades onco / hematológicas, mayores de 14 años, sometidos

a TCMH alogénico fueron evaluados diariamente por la presencia y clasiﬁcación de OM, nivel de dolor, disfagia,

disgeusia y xerostomía. El examen comenzó dos días antes de la infusión de células madre hematopoyéticas y

ﬁnalizó veinte días después. La OM se clasiﬁcó de acuerdo con la escala de la OMS y se utilizó la escala analógica

visual (EVA) para medir el nivel de dolor. Resultados: se reclutaron 23 individuos, el 83% con enfermedades

malignas y el 91% con OM. La mediana del grado máximo de OM fue 3 y el nivel máximo de dolor fue 9. Hubo una

mediana de 11 días de uso de medicación opioide. Los sujetos que tuvieron el mayor número de días con dolor en

la boca alcanzaron el grado máximo de OM y el mayor número de días y el uso de opioides. Conclusión: Hubo una

alta incidencia y puntuaciones más altas de OM, pérdida de masa corporal y dolor en esta muestra.

PALABRAS CLAVE

Mucositis Oral; Trasplante de células madre; Neoplasmas hematológicos.

ABSTRACT

Aim: To describe the oral mucositis (OM)` incidence and score, and related morbidities in individuals submitted

to Hematopoietic Stem Cell Transplantation (HSCT) throughout the immunosuppression period of time Methods:

Subjects with onco / hematological diseases, older than 14 years, submitted to allogeneic HSCT were daily evaluated

by the presence and classiﬁcation of OM, pain level, dysphagia, dysgeusia and xerostomia. The examination

started two days before the infusion of hematopoietic stem cells and ended twenty days later. The OM was classiﬁed

according to the WHO scale and visual analog scale (VAS) was used to measure pain level Results: Twenty-three

individuals were recruted, 83% with malignant diseases and 91% had OM. The median of maximum OM degree

was 3 and the maximum pain level was 9. There was a median of 11 days of opioid medication use. The subjects

who had the highest mean number of days with mouth pain reached the maximum degree of OM and higher

number of days and opiod use. Conclusion: There was a high incidence and high scores of OM, loss of body mass

and pain in this sample.

KEY WORDS

Oral mucositis; Stem Cell Transplantation; Haematological neoplasms.

Recibido: 22 agosto, 2018

Aceptado para publicar: 14 noviembre, 2018

Eurich, C., Pinheiro, C., Kanaan, S., Silva, G. M., Amenábar, J. M. & Carvalho, C. (2019). Evaluación longitudinal de la

mucositis oral en el trasplante de células madre hematopoyéticas: un estudio piloto. Odontología Vital, 1(30), 31-38.

https://doi.org/10.59334/ROV.v1i30.132

Odontología Vital Enero-Junio 2019. Volumen 1 No. 30 Año 17 ISSN 2215-5740

https://doi.org/10.59334/ROV.v1i30.132

32 ODONTOLOGÍA VITAL ENERO - JUNIO 2019

INTRODUCTION

The Hematopoietic Stem Cell

Transplantation (HSCT) is a thera-

peutic procedure to treat onco /

hematological diseases (Armitage,

1994; Lange et al., 2006; Ribeiro

et al., 1996; Ruiz-Argüelles et al.,

2015). Prior the infusion of hema-

topoietic stem cells, an immuno-

suppressant regimen is necessary

for death of bone marrow cells

and preparation for reconstitution

(Armitage, 1994; Bacigalupo et al.,

2009). The most often condition-

ing regimens used for HSCT are

reduced-intensity conditioning

(RIC) and myeloablative (MA), and

both can induce OM (Bacigalupo

et al., 2009; Bardellini et al., 2013;

Chaudhry et al., 2016; Turner et al.,

2010). OM is an inﬂammation of

gastrointestinal tract mucosa and

its main cause is the chemothera-

peutic conditioning prior to HSCT

(Haverman et al., 2014; Stephen

T Sonis, 2012; Stephen T. Sonis,

2012). OM can leave malnutrition,

bacteremia, psychological altera-

tions, increase of hospitalization

days and, often, failure to ﬁnish

immunosuppressant regimen

(Haverman et al., 2014; Peterson et

al., 2011; Vera-Llonch et al., 2007)

. OM is commonly evaluated by

World Health Organization (WHO)

Scale, which considers objective

and subjective variables (WHO,

2017).

Although there are several clini-

cal studies about OM, few studies

evaluate OM daily during the im-

munosuppressant period. In order

to establish strategies to improve

the patient’s quality of life during

the immunosuppressive phase it is

required to evaluate the OM degree

and its consequences throughout

this period. Therefore, the aim of

this study was to describe the in-

cidence, severity of oral OM and

related morbidities in individuals

submitted to HSCT throughout the

immunosuppression period.

METHODS

DESIGN

This is a longitudinal descriptive

study conducted at the Bone Mar-

row Transplantation Unit of the

Hospital de Clínicas of Federal

University of Parana, Curitiba, Pa-

rana, Brazil, and was approved by

the local Research Ethics Review

Committee ( number: 1.431.294).

Individuals’ recruitment was per-

formed when they were at the be-

ginning of the conditioning regi-

men prior to HSCT.

SUBJECTS

Individuals with onco / hema-

tological diseases, older than 14

years, both gender submitted to al-

logeneic HSCT were invited to par-

ticipate of the study.

The participants agreed and signed

the Free and Informed Consent

Term / Informed Assent Term.

Data were collected from March to

October 2016.

PROCEDURE

A trained dentist evaluated all par-

ticipants. The presence and grade

Table 1: Patients characteristics about medications,

disease and transplantation.

VARIABLE n (%)

Sex

Male

Female

12 (52)

11 (48)

Disease

Malignant

Benign

19 (83)

4 (17)

Conditioning regimen

Myeloablative

Reduced Intensity Conditioning

21 (91)

2 (9)

Medications before HSCT

Chemotherapy

Immunosuppression

Tirosin Kinase Inhibitor

Azacitidin

No treatment

15 (65)

3 (13)

2 (9)

1 (4)

2 (9)

Transplantation type

Relatated Donor

Non-Related Donor

Haploidentical

11 (48)

10 (42)

2 (10)

HSCT source

Bone Marrow

Peripheral Blood

19 (83)

4 (17)

Immunoprophylaxis

CSA + MTX

CSA + MMF + CFA

20 (87)

3 (13)

Presence of oral mucositis

Yes

21 (91)

2 (9)

ECSA = Cyclosporin; MTX= Methotrexate; MMF= Mycophenolate; CFA= Cyclophospha-

mide.

Odontología Vital Enero-Junio 2019. Volumen 1 No. 30 Año 17

33ENERO - JUNIO 2019 ODONTOLOGÍA VITAL

of OM, pain level, dysphagia, dys-

geusia and xerostomia were as-

sessed daily. The examination

started two days before the infu-

sion of hematopoietic stem cells

and ended twenty days later. At

the ﬁrst day, all patients received

oral hygiene and OM care instruc-

tions. The OM was classiﬁed ac-

cording to the WHO scale13 and

visual analog scale (VAS) was used

to measure pain level. The partici-

pants answered questions about

dysphagia, dysgeusia and xerosto-

mia. Clinical records were used to

collect demographical data and to

Table 2: Alterations between the grade of Oral Mucositis

RAL MUCOSITIS GRADE

0 II III IV

Cases (n) 2 4 9 8

Sex (n)

Male

Female 2

Previous chemotherapy (n)

Yes

No 2

Conditioning regimen (n)

TBI 1340+CFA

BUS 16+CFA

BUS12+CFA

RIC

Others

Oral Complains (%)

Dysphagia

Dysgeusia

Xerostomia

100

33.3

100

88.9

66.7

100

Days with oral pain (mean±SD) 0 10±3.1 14±4 19±3.4

Days with OM (mean±SD) 0 12±12.6 15±5.1 19±3.5

Opiods (mean±SD)

Maximum dose(mg/day/ IV)

Days of use 3

125±10

9±3.2 40±12.6

12±4.7 71±6.1

15±3.2

BMI (mean±SD) *

Initial

Final

Difference (Final – Initial)

21.8±1.4

21.9±1.5

0.13±0.1

30±6.3

28.3±5.6

- 1.4±0.9

23.6±6.9

22.1±6.1

- 2.3±1.2

28.1±8.9

25.5±7.4

- 3±1.5

Hospitalization time

(in days, mean±SD) 39±19.8 36±7.5 36±4.4 37±4.6

BMI= Body Mass Index; TBI 1320= Total Body Irradiation 1320 rads; CFA =

Cyclophosphamide 120 mg/Kg; BUS 12/16= Busulfan 12/16 Mg/Kg; Fin.=ﬁnal;

In.=Initial * = p>0,05 ANOVA

verify hematological disease, med-

ications, patient’s diet and Body

Mass Index (BMI).

DATA ANALYSIS

Data were tabulated and organized

using Software Statistical Pack-

age for the Social Sciences (SPSS)

20.0. The Shapiro Wilk tests were

used to verify the normality of the

sample. Variance Analysis (ANOVA)

and post hoc of Tukey were used to

compare the BMI with maximum

degree of OM. For statistic signiﬁ-

cant results was considered p <0.05.

RESULTS

The initial sample was composed

of 25 participants, of whom two

were excluded. One had septic

shock and the other one refused

to participate. The median age was

31 years old (min. 14- max. 55) and

male adults were predominant in

the sample (52%). The majority of

individuals had malignant diseases

(83%) and MA conditioning (91%).

Sixty ﬁve percent of the partici-

pants underwent chemotherapy

prior the HSCT. Regarding the type

of transplantation, 11 were related

34 ODONTOLOGÍA VITAL ENERO - JUNIO 2019

donor (48%), the main source used

was the bone marrow (83%) and

the most common immunopro-

phylaxis regimen was Ciclosporin

+ Methotrexate (Table 1).

The incidence of OM was 91% (Ta-

ble 1). The median number of days

with OM among individuals was

14 days (min. 0 – max. 26 days),

while the median number of days

with oral pain was 13 days (min. 0 –

max. 25 days). On the other hand,

the median OM grade, according

to the WHO scale, was 3 (min. 0 –

max. 4) and the maximum pain le-

vel was 9 (min. 0 – max. 10). Opioid

medication was used for 11 days

(min. 0- max. 21) and maximum

dose used was 42 mg / day / EV

(min. 0- max. 80mg / day / EV).

The result of these variables can be

found on chart 1.

Based on the WHO scale, most of

the participants had a maximum

grade 3 (39%) of OM, individuals

with this maximum degree of OM

had mean of days of hospitaliza-

tion similar to the mean of the

other scores. Most individuals with

grade 3 and 4 OM underwent che-

motherapy prior to HSCT (Table

2). The individuals who had the

highest number of days with oral

pain were also those who reached

the maximum score of OM (19

days), stayed more days with OM,

used opioid medication for more

days (mean of 15 days ± 3.2) with

higher doses (mean maximum 71

mg / Day EV ± 6.1). (Table 2).

The conditioning that had the

highest average number of individ-

uals with grade 4 OM was Busulfan

(BUS) 16 mg/kg + Cyclophospha-

mide (CFA) 120mg/kg. (Table 2).

All individuals who had OM also

had BMI reduction during the

follow-up period. The mean loss

of body mass from the beginning

of hospitalization to the end was

higher in individuals who reached

-2

0 0 0 0 0

1 1 23

6 6

7 7

30 30 30 30

31 3232

5 5 5

3 3 3 3 3 3 3 3 3

2 2 2 2

1 1

0 0 0 0 0 0

-1 0 1 2 3 4 5 6 7 8 109

Days

Pain

Measurement

OpioidOM Degree

11 12 13 14 15 16 17 18 19 20

0.5

-0,5

-1

-1,5

-2,5

-2

-3

-3,5

-4

-4,5

-5 0 1 2 3 4

Oral Mucositis Grade

-Body Mass Index

Table 3: Mean days with mucositis, pain and opioid medication

according to conditioning regimens.

Conditioning TBI 1320

+CFA

BUS 16+CFA BUS12+CFA OTHERS

Days with OM

(mean+SD)

2 4 9 8

Days with mouth pain

(mean+SD) 2

Days of opioid use

(mean+SD)

12±3.4 15±3.8 5±3.7 9±6.3

Chart 1 Median of days with oral pain, oral mucositis (degree)

and opioid medication.

Chart 2 Mean of Body Mass Index difference on each

oral mucositis grade

Odontología Vital Enero-Junio 2019. Volumen 1 No. 30 Año 17

35ENERO - JUNIO 2019 ODONTOLOGÍA VITAL

grade 4 OM. However, there was

no statistical signiﬁcance (p>0.05

ANOVA). On the other hand, the

two patients without OM had an

increase in BMI. (Chart 2)

The individuals who had the high-

est mean number of days with OM

and oral pain were those who had

total body irradiation (TBI) 1320

rads + cyclophosphamide (CFA)

120 mg / kg as conditioning (Table

3).

In addition to the opioid, which

all patients with OM received, the

most used treatment for OM was

low-level laser associated with

chamomile tea (52%) (Chart 3).

Topical treatments for OM were

individualized according to the

preferences and possibility of each

subject, regarding the severity of

OM, individual values, socioeco-

nomic condition and above all the

patient’s will.

DISCUSSION

The present study proposed to

evaluate the incidence and degree

of OM, and disorders related to it

Chamomile tea

Chamomile tea + Benzidamine

Chamomile tea + Malvatricin + Benzidamine

Chamomile tea + Low-Level laser

26%

18%

52%

Chart 3 Distribution of the different treatments used by

the patients for oral mucositis.

in individuals submitted to allo-

geneic HSCT. The most important

ﬁndings were the high incidence

OM and the correlation between

the OM severity degree, according

to WHO scale, with the use of opi-

oid medication and BMI. Individu-

als with higher OM scale values

needed more opioid medication

and lost more weight.

OM is a frequent condition in indi-

viduals submitted to HSCT, which

affects their quality of life (Silva et

al., 2015; Vera-Llonch et al., 2007).

In the present sample there were a

great number of participants with

leukemia, consequently, the con-

ditioning regimens were mostly

MA, which could explain the high

incidence of OM (Eslami et al.,

2016; Ramírez-amador et al., 2010;

Small et al., 2007; Wojciechowicz et

al., 2014).

The use of MTX as immunopro-

phylaxis may also have been a

contributing factor to OM high

incidence due to its high cytotoxic

potential in cells with rapid mul-

tiplication. In addition, MTX is

responsible for the delay of repair

of the tissue damaged by chemo-

therapeutic conditioning (Ahmed

et al., 2017; Cutler et al., 2005; Knoll

et al., 2016; Matsukawa et al., 2016;

Ramírez-amador et al., 2010; Small

et al., 2007).

When compared to the total of

days of hospitlization, a signiﬁcant

average of days with OM, oral pain

and opioid medication were dem-

onstrated. This average changes

when participants are segregated

according to the maximum OM

grade: Grade 4 individuals were

affected with longer periods with

OM, had more oral pain, more opi-

oid using and with higher dosage

than patients with lower scores.

There was a greater BMI loss in pa-

tients who reached grade 3 and 4

OM, although no statistical signiﬁ-

cance was detected (Table2).

Regarding the conditioning regi-

men, individuals who used BUS

16 or TBI 1320 had a higher degree

of OM (Table 1). Although most of

the participants with grade 3 and 4

OM used BUS 16, who had a longer

mean of days with OM and mouth

pain were those that conditioned

with TBI 1320, which suggests that

such conditioning leads to pro-

longed toxicity. On the other hand,

Chaudhry et al.(2016) performed a

systematic review that evaluated

the incidence and severity of OM

in HSCT and found that there was

a signiﬁcant incidence of severe

OM in both MA and RIC and those

individuals who received TBI had

more severe OM when compared

to BUS. Nevertheless, it is impor-

tant that individuals undergoing

these types of conditioning receive

extra oral.

Concerning the functional altera-

tions in the mouth, there was a

high incidence of dysgeusia and

xerostomia in patients with grade

3 and 4 OM (Table 2). Boer (Boer

et al., 2009) already evaluated the

36 ODONTOLOGÍA VITAL ENERO - JUNIO 2019

taste alteration of patients sub-

mitted to HSCT and veriﬁed that

the situation continues as a late

complication. Furthermore, Laak-

sonen et al.(Laaksonen et al., 2011)

studied longitudinally the saliva of

patients for 24 months after HSCT,

and also demonstrated some func-

tional alteration in the mouth,

concluding that hyposalivation is

frequent and occurs more in MA

conditioning and is reversible.

It is important to note that the use

of opioid medication may often be

associated with other painful epi-

sodes, not necessarily OM, so, it is

important to evaluate other param-

eters, such as evaluation of mouth

pain by VAS and the score of OM

by the scale of WHO. Moreover,

BMI should be used judiciously,

especially in individuals with lean

mass and / or water retention. In

future studies it is suggested that

body composition should be con-

sidered similarly to the study by

Thomaz (ABESO, 2016; Thomaz et

al., 2015).

One limitation of this study is the

small number of participants. Fur-

ther studies with higher sample

size are suggested to evaluate the

risk factors for OM and thus to de-

lineate a line of care for this condi-

tion.

Although OM is a self-limiting con-

dition and resolves with decreas-

ing of chemotherapy toxicity and

consequent bone marrow regen-

eration, it is still a debilitating con-

dition. Therefore, it is important

to delimit its incidence, severity,

risk factors and evolution time, for

oral care can be implemented in

the population at risk, in order to

decrease the use of opioid medica-

tion and its side effects, improving

the quality of life of this group.

CONCLUSION

A high incidence of severe oral OM

was observed in this population

during this period of time. Indi-

viduals with a maximum grade of

OM 3 and 4 and greater dosages

and longer time of opioid analge-

sia use.

Authors

Carolina Eurich Mazur DDS1; Camila Pin-

heiro Furquim DDS, MSc1; Samir Kanaan

Nabhan MD2 ; Geisla Mary Silva Soares

DDS, PhD 1; José Miguel Amenábar DDS,

PhD1; Cassius Carvalho Torres-Pereira

DDS, PhD1

1 Department of Stomatology, Gradu-

ation Program in Dentistry. Federal

University of Parana.

2 Bone Marrow Transplantation Unit,

Hospital de Clínicas. Federal University

of Parana

Author: Carolina Eurich Mazur

E-mail address: carolmazur6@hotmail.

com

Cellphone number: +55 042 99291581

Address: Rua Doutor Corrêa Coelho –

744 – Edíﬁcio Jardim Botânico, Jardim

Botânico, Curitiba, Paraná, Brasil – CEP:

80210-350.

Brasil

Odontología Vital Enero-Junio 2019. Volumen 1 No. 30 Año 17

37ENERO - JUNIO 2019 ODONTOLOGÍA VITAL

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