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Photomedicine and Laser Surgery
Volume 27, Number 1, 2009
© Mary Ann Liebert, Inc.
Pp. 137–144
DOI: 10.1089/pho.2007.2225
Case Report
Severity of Oral Mucositis in Patients Undergoing
Hematopoietic Cell Transplantation
and an Oral Laser Phototherapy Protocol:
A Survey of 30 Patients
Fernanda de Paula Eduardo, D.D.S., M.S.D., Ph.D.,
1
Leticia Bezinelli, D.D.S.,
1
Ana Claudia Luiz, D.D.S., M.S.D.,
1
Luciana Correa, D.D.S., M.S.D., Ph.D.,
2
Cristina Vogel, R.N.,
1
and Carlos de Paula Eduardo, D.D.S., M.S.D., Ph.D.
3
Abstract
Background Data and Objective: Oral mucositis (OM) is one of the worst cytotoxic effects of chemotherapy
and radiotherapy in patients undergoing hematopoietic cell transplantation (HCT), and it causes severe mor-
bidity. Laser phototherapy has been considered as an alternative therapy for prevention and treatment of OM.
The aim of this study was to describe the incidence and severity of OM in HCT patients subjected to laser pho-
totherapy, and to discuss its effect on the oral mucosa.
Patients and Methods: Information concerning patient age and gender, type of basic disease, conditioning reg-
imen, type of transplant, absence or presence of pain related to the oral cavity, OM grade, and adverse reac-
tions or unusual events were collected from 30 patients undergoing HCT (allogeneic or autologous). These pa-
tients were given oral laser phototherapy with a InGaAIP laser (660 nm and 40 mW) daily. The data were
tabulated and their frequency expressed as percentages.
Results: In the analysis of those with OM, it was observed that 33.4% exhibited grade I, 40% grade II, 23.3%
grade III, and 3.3% grade IV disease. On the most critical post-HCT days (D5 and D8), it was observed that
63.3% of patients had grade I and 33.3% had grade II disease; no patients had grade III or IV disease in this
period. This severity of OM was similar to that seen in other studies of laser phototherapy and OM.
Conclusion: The low grades of OM observed in this survey show the beneficial effects of laser phototherapy,
but randomized clinical trials are necessary to confirm these findings.
137
Introduction
O
RAL MUCOSITIS
(OM) is the most common sequela in pa-
tients subjected to chemotherapy and radiotherapy fol-
lowing hematopoietic cell transplantation (HCT). It consists
of ulcerated lesions on the oral mucosa, and is characterized
by fragility and loss of epithelial continuity, bleeding, edema,
and exposure and necrosis of the lamina itself, either with
or without formation of a pseudomembrane, and secondary
contamination.
1,2
These lesions are accompanied by a sig-
nificant increase in days of fever and risk of infection, par-
ticularly in neutropenic patients,
3
in addition to causing ad-
ditional days of parenteral nutrition requirement and a need
for intravenous narcotics because of the intense pain.
4
It has
been reported that cancer therapy has had to be changed or
interrupted due to the extensive morbidity caused by OM.
5
Patients that develop OM during HCT have noted that it is
a side effect having great impact on the process of their re-
covery.
Generally, in patients subjected to HCT, 75–85% develop
OM, and the incidence is higher in patients that receive re-
peated doses of melphalan and chemotherapy associated
with total body irradiation.
4,6
OM appears in the second
week of HCT and peaks between the seventh and 11th days
post-HCT.
1,7
The lesions regress by the 20th day, unless
graft-versus-host disease (GVHD) arises in those receiving
allogeneic transplants.
7
Alternative treatments to prevent or treat OM are being
studied.
8,9
These include natural agents, cryotherapy,
10,11
antimicrobial agents,
12
anti-inflammatory medications,
13
1
Hospital Israelita Albert Einstein, Unit of Bone Marrow Transplantation,
2
Department of General Pathology, School of Dentistry, Uni-
versity of Sao Paulo, and
3
Department of Restorative Dentistry (LELO—Special Laboratory of Lasers in Dentistry), School of Dentistry,
University of Sao Paulo, Sao Paulo, Brazil.
growth factors such as those for keratinocytes
14
and for mac-
rophages and granulocytes,
15
and laser phototherapy with
various protocols, as shown in Table 1.
1,7,8,16–25
In 2004, and updated in 2007, the Multinational Associa-
tion of Supportive Care in Cancer and the International So-
ciety for Oral Oncology established guidelines for the treat-
ment and prevention of oral mucositis, based on a careful sur-
vey of the literature on the subject.
4,26
Among the guidelines
written by this group, it is notable that they indicated that for
severe chemotherapy treatments such as those given to HCT
patients, laser phototherapy was recommended to prevent ul-
cerated lesions and to treat the intense pain of OM.
4,16
EDUARDO ET AL.138
T
ABLE
1. P
ROTOCOLS FOR
L
ASER
P
HOTOTHERAPY FOR
P
REVENTION AND
/
OR
T
REATMENT
OF
C
HEMOTHERAPY
-
AND
R
ADIOTHERAPY
-I
NDUCED
O
RAL
M
UCOSITIS
No. of Type of Duration of Oral application
Authors patients analysis Laser protocol laser therapy sites
Barasch et al.
17
11 (aged Modified IMO He:Ne, 632.8 40 sec per site R
22–55 y) and oral nm, 25 mW, for 5 consecutive BM, LP, TO, SP, FM
toxicity scale 1.0 J/cm
2
days (2 d before
(by ECOG), transplantation)
VAS
Cowen et al.
7
30 (aged IMO He:Ne, 632.8 10 sec per site, R/L
17–58 y) (including SP, nm, 60 mW, once per day for BM, LP, TO, GI
SSP) 1.5 J/cm
2
5 consecutive
days
Bensadoun et 30 patients IMO (by He-Ne, 632.8 33 sec or 80 sec SP, OP
al.
19
(aged WHO), VAS nm, 60 mW or at nine points,
36–78 y) 25 mW, 2 for 5 consecutive
J/cm
2
days starting 7
weeks before
radiotherapy
Wong and 15 patients IMO (by NIS, 45–50 Weekly for R/L
Wilder-Smith
18
(18 y of WHO), VA, mW; total dose 15–20 min, 24 h BM, LP, TO, SP, GI
age LDF 50–60 J (0.7 or before the end of
0.8 J/cm
2
) treatment, or
until remission
of lesions
Migliorati et 11 patients IMO (by GaAlAS, 780 35 min daily Not specified
al.
1
(aged WHO), VAS nm, 60 mW, from D5 to
10–75 y) 2 J/cm
2
D5
Bensadoun and 30 patients IMO (by He:Ne, 632.8 5 consecutive SP, TP, OP
Ciais
8
(aged WHO), VAS nm, 60 mW, days during 7 wk
36–78 y) 2 J/cm
2
of radiotherapy
Sandoval et 18 (aged IMO (by NCI), NIS, 660 nm, Daily until Only on the lesions;
al.
20
4–82 y) VAS 30 mW, lesions resolved, oral sites not
2 J/cm
2
1 min; mean of specified
5.33 applications
per patient
Arun Maya 50 patients IMO (by He-Ne, 632.8 Daily, 3 min for SP, OP
et al.
21
mean age WHO), VAS nm, 10 mW 5 d in one week
53 1 y)
Corti et al.
22
24 (aged IMO
40
, VAS LED, 645 nm, 5 min, 3 times/d, Directly on the zone
20–82 y) 7.8 mW, 0.99 for 7 consecutive of mucositis
J/cm
2
days
Cruz et al.
23
60 (aged IMO (by NCI) NIF, 780 nm, 5 consecutive BM, LI, TO, SP, FM
3–18 y). 60 mW, days after
4 J/cm
2
chemotherapy
Antunes et al.
24
38 patients IMO (by InGaAIP, 660 16.7 sec at each R/L
(average WHO), VAS nm, 50 mW, point, from D–7 BM, LP, TO, SP,
age 36.5 y) 4 J/cm
2
until neutrophil HP, FM
recovery
Schubert et al.
16
70 (aged IMO, VAS GaAlAs, Daily for 7–13 d R/L
18–69 y) 650–780 nm, (D7 to D2) BM, LP, TO, SP,
40–60 mW, HP, FM
2 J/cm
2
IMO, daily oral mucositis index; ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization; VAS, visual analogue
scale of pain; SP, pain scale; SSP, swallowing scale of pain; LDF, laser Doppler flowmetry; NCI, National Cancer Institute; NIS, no indication
of source; R, right side; L, left side; BM, buccal mucosa; LP, lips; TO, tongue; Sp, soft palate; HP, hard palate; FM, floor of mouth; GI, gingiva;
OP, oropharynx.
The aim of this study was to describe the incidence and
severity of OM in HCT patients subjected to laser pho-
totherapy.
Patients and Methods
The study involved 30 patients who were subjected to HCT,
and admitted to the Hospital Israelita Albert Einstein, São
Paulo, Brazil, between January 2006 to January 2007, who were
at high risk for developing OM as a result of pre-HCT condi-
tioning. At this hospital, laser phototherapy is a part of the
treatment protocol for these patients, in an effort to prevent
and treat oral lesions caused by HCT conditioning, especially
OM. By consulting our medical database, we collected med-
ical and dental data for our patients, and chose those that fit
the following criteria for this study: a desire to undergo the
proposed laser therapy protocol, and agreement to comply
with the oral hygiene regimen we recommended. Informed
consent was obtained from all participants. Patients receiving
drugs or other agents to prevent mucositis, and those involved
in other protocols were excluded. The study was approved by
the Ethics Committee of the hospital.
The oral hygiene routine involved brushing with a soft-
bristled toothbrush, use of an alcohol-free mouthwash with
enzymatic action (Biotene
®
; Laclede, Inc., Rancho Dominguez,
CA), lip hydration, and daily confirmation that they com-
plied with the oral hygiene regimen.
The laser we used to carry out our therapeutic protocol
was an InGaAIP (indium-gallium-aluminum-phosphide) low-
intensity diode laser (MMOptics, São Carlos, Brazil) emitting
in the red visible wavelength (660 nm) at 40 mW of power,
with an energy density of 4 J/cm
2
(for prevention of ulcer-
ated lesions in the oral cavity), or 6 J/cm
2
(for treatment of
those with confirmed ulcerations), with a spot size of 0.036 cm
2
.
Daily laser phototherapy sessions were conducted begin-
ning on the first day of pre-HCT conditioning. Treatment was
continued until the day of marrow transplantation (with an
absolute neutrophil count 0.5 10
9
/L), or until the patient
no longer had any ulcerated lesions in the oral cavity. The
overall leukocyte count was also used as a criterion for de-
termining the end of laser phototherapy. If there was a rising
number of leukocytes, or when the number attained a mean
value close to the point at which the bone marrow could be-
gin making more leukocytes, and if there were no ulcerated
lesions in the oral cavity, laser phototherapy was terminated.
Before and after each session, the laser was checked with
a power meter (Coherent, Inc., Santa Clara, CA, USA) to ver-
ify that the output was consistent. Three calibrated opera-
tors performed this adjustment daily.
Nine anatomic areas that had the highest incidence of mu-
cositis
18
were treated by three dentists trained in adminis-
tering laser treatment. The treated areas included: the lower
and upper lip and lower labial mucosa, the right and left ju-
gal mucosa, the lateral borders of the tongue, the ventral part
of the tongue, and the floor of the mouth.
Both the patients and the operators wore protective glasses
designed for the wavelength our laser emitted for the entire
period that the laser was activated, and routine biosafety pro-
cedures were followed.
Data including patient age and gender, the type of dis-
ease, the conditioning regimen, the type of transplant, ab-
sence or presence of pain in the oral cavity, OM grade, and
adverse reactions or unusual events were recorded. The
severity of mucositis was determined in accordance with the
functional grading established by the World Health Organi-
zation.
27
Afterward, the data were tabulated and quantified,
and the percentages at which the studied parameters oc-
curred were calculated.
Results
Table 2 contains the data of the selected patients with re-
gard to gender, age, diagnosis, conditioning regimen, doses,
and number of days the medication was used. The patients’
ages ranged from 8–72 y, with most being concentrated in the
age ranges from 41–50 y (30%), 51–60 y (23.3%), and 21–30 y
(20%). Of these 53.3% were women. With regard to diagno-
sis, 46.7% had non-Hodgkin’s lymphoma, 23.3% had Hodg-
kin’s lymphoma, and 20% had acute myeloid leukemia. The
others presented with chronic myeloid leukemia (6.7%) and
acute lymphocytic leukemia (3.3%). The most frequently used
chemotherapy conditioning regimen was the combination of
cyclophosphamide, etoposide, and carmustine (12 patients,
40.0%), followed by the combination of carmustine, etopo-
side, cytarabine, and melphalan (5 patients, 16.7%) and flu-
darabine and busulfan (3 patients, 10.0%). The other patients
had combinations cyclophosphamide and total body irradia-
tion (TBI) (4 patients, 13.3%) and fludarabine and melphalan
(2 patients, 6.66%), one patient (3.33%) had these drugs with
mabthera and thyotepa and one other had melphalan.
The autologous transplant was the most frequently used
(63.3%) and the balance had allogeneic transplants (36.7%)
(Table 3). In all patients who had allogeneic transplants,
methotrexate was administered to prevent GVHD. In this
group, it was observed that 6 patients developed grade II
OM as maximum severity of mucositis, and 3 patients had
grade I; 2 and 2 patients exhibited grades III and IV, re-
spectively. The time that it took for the bone marrow to take
hold in all 30 patients was between D8 and D26, with a
mean of 12.6 d.
Table 3 shows the number of laser phototherapy sessions
and the maximum degree of mucositis for each patient. A
mean 18.2 sessions were performed in all. In 2 patients (6.6%)
the laser phototherapy sessions were conducted beyond the
period when the bone marrow took hold (it was exceeded
by 2 or more days), whereas in 7 patients (23.3%) the oppo-
site was true (the laser sessions ceased at least 2 days before
this occurred). Only one patient (3.3%) developed grade IV
OM, and 7 (23.3%) exhibited grade III OM. Grade I was pres-
ent in 10 patients (33.4%), and grade II was present in 12 pa-
tients (40%).
Four patients (patients 2, 8, 16, and 17), whose chemo-
therapy conditioning was a combination of carmustine, cy-
clophosphamide, and etoposide, developed grade III OM;
three of these patients had a reduction in the degree of mu-
cositis on D5 and D8. Mucositis grade III was observed
in one patient (patient 23), in whom the chemotherapy com-
bination involved etoposide, carmustine, cytarabine, and
melphalan; this patient also exhibited a reduction in degree
on D5 and D8. Two patients subjected to fludarabine and
busulfan exhibited mucositis grade III (patient 17) and grade
IV (patient 25, between D14 and D16); in both there was
a reduction in the degree of mucositis, although patient 25
still had grade III mucositis on D5 and D8. This patient
LASER PHOTOTHERAPY FOR MUCOSITIS 139
EDUARDO ET AL.140
T
ABLE
2. P
ATIENT
D
EMOGRAPHIC
D
ATA
, D
IAGNOSIS
, C
HEMOTHERAPY OR
R
ADIOTHERAPY
R
EGIMEN AND
D
OSE
Patient Total dose
no. Age Sex Diagnosis Regimen (mg) Conditioning period
1 51 F AML Fludarabine 288 D–6 to D–3
busulfan 960 D–6 to D–3
2 40 F NHL Cyclophosphamide 9900 D–7 to D–5
carmustine 500 D–7
etoposide 2640 D–7 to D–4
3 43 M ALL Cyclophosphamide 6800 D–3 and D–2
TBI 1200 cGy D–6 to D–4
methotrexate 75.6
4 31 M NHL Cyclophosphamide 12,600 D–7 to D–5
carmustine 630 D–7
etoposide 1680 D–7 to D–4
5 56 M NHL Carmustine 570 D–7
etoposide 1520 D–7 to D–4
cyclophosphamide 11,340 D–7 to D–4
6 59 F NHL Carmustine 490 D–7
etoposide 2560 D–7 to D–4
cyclophosphamide 9840 D–7 to D–5
7 66 F AML Fludarabine 199 D–7 to D–3
melphalan 220 D–2
8 70 F NHL Cyclophosphamide 9000 D–7 to D–4
carmustine 350 D–7
etoposide 1200 D–7 to D–5
9 51 M NHL Cyclophosphamide 9000 D–6 and D–5
TBI 1200 cGy D–4 to D–2
10 42 M HL Carmustine 570 D–7
cytarabine 3040 D–7 to D–4
etoposide 2280 D–7 to D–4
melphalan 266 D–3
11 25 F HL Cyclophosphamide 12,000 D–7 to D–5
carmustine 600 D–7
etoposide 1600 D–7 to D–4
12 44 M NHL Cyclophosphamide 9900 D–7 to D–5
carmustine 495 D–7
etoposide 2640 D–7 to D–4
13 46 F NHL Cyclophosphamide 11,100 D–7 to D–5
carmustine 560 D–7
etoposide 2960 D–7 to D–4
14 47 M NHL Carmustine 525 D–8
etoposide 1750 D–8 to D–4
cyclophosphamide 4500 D–8 to D–6
15 23 F HL Cyclophosphamide 9360 D–7 to D–5
carmustine 460 D–7
etoposide 2480 D–7 to D–4
16 29 F HL Carmustine 540 D–7
etoposide 2880 D–7 to D–4
cyclophosphamide 10,800 D–7 to D–5
17 52 M HL Cyclophosphamide 9900 D–7 to D–5
carmustine 400 D–7
etoposide 2640 D–7 to D–4
18 8 M CML Busulfan 336 D–7 to D–4
cyclophosphamide 2520 D–3 to D-2
thymoglobulin 945 D–3 to D–1
19 28 F AML Fludarabine 232 D–6 to D–2
busulfan 760 D–6 to D–2
20 35 F HL Carmustine 560 D–7
etoposide 1480 D–7 to D–4
cytarabine 2960 D–7 to D–4
melphalan 259 D–3
21 23 M CML Cyclophosphamide 11,200 D–7 to D–6
TBI 1370 cGy D–4 to D–1
22 50 M NHL Carmustine 540 D–6
cytarabine 2880 D–6 to D–3
melphalan 250 D–2
etoposide 1440 D–6 to D–3
exhibited intense pain on deglutition on D8, when par-
enteral nutrition was started. In spite of having mucositis
grade III, the oral mucosa did not show any ulceration. One
patient subjected to melphalan treatment (patient 24) did not
have a reduction in the degree of mucositis (grade III) on
D8; this was a kidney transplant patient with a previous
history of chemotherapy and mucositis. Mucositis grade II
remained in the period from D8 to D14.
The patients subjected to total body irradiation at a total
dose of 1200 cGy (patients 3, 9, 21, and 26) had allogeneic
transplants, with cyclophosphamide. Of these patients, 3 had
grade II as the maximum mucositis grade, and one patient
had grade I. These degrees were also maintained on D5
and D8 (Table 4).
No patients experienced any symptoms or alterations in
oral mucosa that would indicate that there were harmful side
effects from the laser phototherapy.
Discussion
The patients in this study were selected primarily for their
HCT conditioning regimen, as we considered them to be at
high risk for developing mucositis (Table 2). The data indi-
cate that few patients developed severe degrees of mucositis
(Table 4). It is well known that all myeloablative regimens re-
sult in some degree of toxicity to the gastrointestinal tract mu-
cosa,
28
and that grades III and IV OM are frequently seen in
such cases, and some patients require parenteral nutrition and
analgesia.
3,26,29
Also, 36.7% of our patients were subjected to
treatment with methotrexate, which is known to produce mu-
cositis even when given at very low doses to prevent GVHD;
4
the majority of these patients had grades I and II mucositis.
There were also four patients in this study submitted to TBI
and chemotherapy associated with HCT, which is a known
risk factor for developing mucositis.
4
As the absence of any
other preventive treatment for mucositis was a selection cri-
terion, one can infer that laser phototherapy might have di-
minished the severity of mucositis in these patients.
Chemotherapy-induced mucositis persists for 10 d on av-
erage, and regresses spontaneously after 21 d post-infu-
sion.
30
As the days of highest risk for mucositis, D5 and
D8 were selected for analysis. It was observed that the ma-
jority of patients exhibited grade I mucositis, both on D5
(63.3%) and on D8 (63.3%). A slight reduction in grade II
mucositis was observed on D8 (30%) in comparison to D5
(33%), and an increase in mucositis to grade III (6.7%) was
also seen. There were no patients with grade IV mucositis in
this period (Table 4).
The authors used a laser phototherapy protocol adapted
from Schubert et al.
16
as preventive treatment; however,
some applied twice the energy, as did Migliorati et al.,
1
for
curative treatment of OM. This protocol adaptation was cho-
sen based on in vitro studies using epithelial cells in culture.
31
The studies described in Table 1 used lower energy doses.
Although there is a consensus about the laser photother-
apy protocol to use to treat mucositis, there is still contro-
versy in the literature with regard to the frequency of irra-
diation, particularly as far as the number of sessions and
duration of each session are concerned. Several studies are
imprecise in describing their irradiation protocols; further-
more, the great variability of clinical conditions, medical his-
tory, and chemotherapy and radiotherapy regimens, as well
as the small number of controlled studies, makes it difficult
to compare studies, particularly with regard to the efficacy
of laser phototherapy in preventing and treating OM.
In our case series, we found that it was important to use
laser every day during the course of the myeloablative reg-
imen. It is also important to observe the oral mucosa care-
LASER PHOTOTHERAPY FOR MUCOSITIS 141
T
ABLE
2. P
ATIENT
D
EMOGRAPHIC
D
ATA
, D
IAGNOSIS
, C
HEMOTHERAPY OR
R
ADIOTHERAPY
R
EGIMEN AND
D
OSE
(C
ONT
’
D
)
Patient Total dose
no. Age Sex Diagnosis Regimen (mg) Conditioning period
23 43 F NHL Carmustine 420 D–1
etoposide 1220 D–2 to D–5
cytarabine 2240 D–2 to D–5
melphalan 196 D–1
24 72 F NHL Melphalan 350 D–4 and D–3
25 45 F AML Fludarabine 64.8 D–6 to D–3
busulfan 216.6 D–6 to D–3
thymoglobulin 113 D–3 to D–1
26 11 M AML Cyclophosphamide 3720 D–5 to D–4
TBI 1200 cGy D–3 to D–1
27 30 F AML Busulfan 760 D–7 to D–4
cyclophosphamide 4400 D–3 to D–2
28 52 F NHL Carmustine 670 D–6
thiotepa 330 D–5 to D–4
rituximab 700 D–6
29 50 M NHL Fludarabine 200 D–6 to D–3
melphalan 245 D–2
rituximab 1750 D–6
30 55 M NHL Carmustine 300 D–7
etoposide 400 D–7 to D–4
cytarabine 1600 D–7 to D–4
melphalan 140 D–3
AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CML, chronic myeloid leukemia; HL, Hodgkin’s lymphoma; NHL, non-
Hodgkin’s lymphoma.
fully to determine when the bone marrow has taken hold,
and to monitor the number of leukocytes, as in patients with
HCT the reparative phase of mucositis is marked by leuko-
cyte recovery.
3
If there are still mucositis lesions present af-
ter the bone marrow has taken hold, or when the patient has
regained adequate levels of leukocytes, it is imperative to
continue laser phototherapy until the lesions disappear.
The application of laser phototherapy as an integral part
of treatment in patients undergoing HCT has shown some
difficulties with regard to the severity of the oral lesions that
are indicative of mucositis. Sonis et al.
32
pointed out that the
main obstacle to developing laser phototherapy regimens to
treat mucositis is the lack of an objective system for grading
mucositis. The grading schemes recommended by the
WHO
27
and the National Cancer Institute
33
characterize the
general state of the health of the patient in relation to the cy-
totoxic effects of chemotherapy and radiotherapy. In these
systems, there is an association between the clinical condi-
tion of the oral mucosa (erythema or ulceration) and the pa-
tient’s capacity to eat, along with the presence or absence of
pain. We believe that the widespread use of one of these
schemes would provide more accurate characterization of
the health of the oral mucosa.
It is important to emphasize, however, that even those
with grade III mucositis did not necessarily have lesions in
the oral cavity. For this reason, analysis of the efficacy of
laser phototherapy in preventing or treating lesions on the
oral mucosa is difficult, since the grading scheme may not
accurately characterize the status of the health of the oral
mucosa.
The use of laser phototherapy in patients at risk for de-
veloping mucositis remains controversial. Studies in the lit-
erature show the efficacy of laser therapy in reducing the
grade in those with grade III and IV mucositis, and for main-
taining patients at grades I and II.
8,23
One of the beneficial
EDUARDO ET AL.142
T
ABLE
3. T
YPE OF
T
RANSPLANT
, D
AY OF
M
ARROW
T
RANSPLANTATION
, N
UMBER OF
T
REATMENT
D
AYS
, N
UMBER OF
L
ASER
T
HERAPY
S
ESSIONS
,
AND
M
AXIMUM
D
EGREE OF
M
UCOSITIS
Maximum
Patient Type of Marrow Number of treatment Number of laser degree of
no. transplant transplantation days
a
therapy sessions mucositis
1 ALLO D12 18 27 Grade II
2 AUTO D22 29 24 Grade III
3 ALLO D19 25 25 Grade II
4 AUTO D9016 15 Grade II
5 AUTO D9016 15 Grade I
6 AUTO D8015 14 Grade I
7 ALLO D11 24 17 Grade I
8 AUTO D10 17 16 Grade III
9 ALLO D14 20 19 Grade II
10 AUTO D9016 15 Grade I
11 AUTO D9016 15 Grade II
12 AUTO D8015 12 Grade II
13 AUTO D10 17 15 Grade II
14 AUTO D10 18 17 Grade I
15 AUTO D10 17 18 Grade II
16 AUTO D12 19 18 Grade III
17 AUTO D11 18 17 Grade III
18 ALLO D26 33 25 Grade II
19 ALLO D18 24 24 Grade III
20 AUTO D10 17 16 Grade I
21 ALLO D16 23 22 Grade II
22 AUTO D11 17 14 Grade I
23 AUTO D17 22 21 Grade III
24 AUTO D11 15 14 Grade III
25 ALLO D18 24 24 Grade IV
26 ALLO D12 17 13 Grade I
27 ALLO D11 18 17 Grade I
28 AUTO D11 17 18 Grade I
29 ALLO D16 22 24 Grade II
30 AUTO D10 17 17 Grade II
a
Time from the initial conditioning regimen until marrow transplantation.
AUTO, autologous transplant; ALLO, allogeneic transplant.
T
ABLE
4. D
EGREE OF
M
UCOSITIS IN THE
C
RITICAL
P
ERIOD FROM
D5
THROUGH
D8
Degree of mucositis D5 (%) D8 (%)
0 0 (0) 0 (0)
I 19 (63.3) 19 (63.3)
II 10 (33.3) 9 (30.0)
III 1 (3.3) 2 (6.7)
IV 0 (0,0) 0 (0)
Total 30 (100) 30 (100)
effects of laser therapy is analgesia.
34,35
Reductions in grades
of mucositis are related to the reductions in pain, and pain
in the oral cavity is one of the worst side effects of chemo-
therapy and radiotherapy.
6
Thus, laser phototherapy may
play a fundamental role in the multidisciplinary treatment
of HCT, by improving the patient’s systemic condition and
reducing hospitalization time.
The laser therapy protocol used is based on the patho-
genesis of mucositis, and the effects of laser phototherapy
on angiogenesis and control of oxidative stress are well
known. It is also well known that the epithelial damage
caused by chemotherapy and radiotherapy is preceded by
endothelial vascular changes.
3
Laser phototherapy has
shown the potential to stimulate angiogenesis,
36
and this
may help heal ulcers, depending on their size.
37
The ap-
pearance of mucositis has also been associated with high lev-
els of TNF-and IL-1
3
. Laser phototherapy appears to di-
minish the levels of TNF-in sites subjected to chronic
stress.
38
The initiating events of mucositis are associated with
reactive oxygen species (ROS) derived from the action of che-
motherapy and radiotherapy, which cause damage to the
DNA, and the activation of transcription factors, among
them nuclear factor-kappa B (NF-B), which in turn gener-
ates the activation of various cytokines (TNF-, IL-1, and
IL-6). Laser phototherapy has demonstrated a blocking ef-
fect on ROS and NF-B activation.
39
It is worth mentioning
that laser phototherapy does not have an antimicrobial ef-
fect, and therefore does not prevent infection, which may oc-
cur in the ulcerative phase of mucositis. To prevent or treat
this, all patients subjected to laser phototherapy need to prac-
tice good oral hygiene with daily use of mouthwash con-
taining the enzymes glucose oxidase, lactoperoxidase,
lysozyme, and lactoferrin.
40
It is important to emphasize that regardless if mucositis
lesions were present, all nine anatomic areas of the oral cav-
ity were subjected to laser phototherapy at each session, as
the therapy was not only curative, but was also preven-
tive.
16,21,22
Conclusion
In this study, we found that laser phototherapy tended to
maintain mucositis levels at grades I and II, which was a pos-
itive effect of laser phototherapy for the treatment of hema-
topoietic cell transplantation patients.
References
1. Migliorati, C., Massumoto, C., Eduardo, F.P., et al. (2001).
Low-energy therapy in oral mucositis. J. Oral Laser Appl. 1,
97–101.
2. Parulekar, W., Mackenzie, R., Bjarnason, G., and Jordan, R.C.
(1998). Scoring oral mucositis. Oral Oncol. 34, 63–71.
3. Sonis, S.T., Elting, L.S., Keefe, D., et al. (2004). Perspectives
on cancer therapy-induced mucosal injury: pathogenesis,
measurement, epidemiology, and consequences for patients.
Cancer. 100(9 Suppl), 1995–2025.
4. Rubenstein, E.B., Peterson, D.E., Schubert, M., et al. (2004).
Clinical practice guidelines for the prevention and treatment
of cancer therapy-induced oral and gastrointestinal mucosi-
tis. Cancer. 100(9 Suppl), 2026–2046.
5. Nes, A.G., and Posso, MB.. (2005). Patients with moderate
chemotherapy-induced mucositis: pain therapy using low
intensity lasers. Int. Nurs. Rev. 52, 68–72.
6. Bellm, L.A., Epstein, J.B., Rose-Ped, A., Martin, P., and
Fuchs, H.J. (2000). Patient reports of complications of bone
marrow transplantation. Support Care Cancer. 8, 33–39.
7. Cowen, D., Tardieu, C., Schubert, M., et al. (1997). Low en-
ergy helium-neon laser in the prevention of oral mucositis
in patients undergoing bone marrow transplant: results of a
double blind randomized trial. Int. J. Radiat. Oncol. Biol.
Phys. 38, 697–703.
8. Bensadoun, R.J., and Ciais, G. (2002). Radiation- and che-
motherapy-induced mucositis in oncology: results of multi-
center phase III studies. J. Oral Laser Appl. 2, 115–120.
9. Migliorati, C.A., Oberle-Edwards, L., and Schubert, M.
(2006). The role of alternative and natural agents, cryother-
apy, and/or laser for management of alimentary mucositis.
Support Care Cancer. 14, 533–540.
10. Gori, E., Arpinati, M., Bonifazi, F., et al. (2007). Cryotherapy
in the prevention of oral mucositis in patients receiving low-
dose methotrexate following myeloablative allogeneic stem
cell transplantation: a prospective randomized study of the
Gruppo Italiano Trapianto di Midollo Osseo nurses group.
Bone Marrow Transplant. 39, 347–352.
11. Svanberg, A., Birgegard, G., and Ohrn, K. (2007). Oral
cryotherapy reduces mucositis and opioid use after mye-
loablative therapy—a randomized controlled trial. Support
Care Cancer. 15, 1155–1161.
12. Barasch, A., Elad, S., Altman, A., Damato, K., and Epstein,
J. (2006). Antimicrobials, mucosal coating agents, anesthet-
ics, analgesics, and nutritional supplements for alimentary
tract mucositis. Support Care Cancer. 14, 528–532.
13. Lalla, R.V., Schubert, M.M., Bensadoun, R.J., and Keefe, D.
(2006). Anti-inflammatory agents in the management of al-
imentary mucositis. Support Care Cancer. 14, 558–565.
14. Beaven, A.W., and Shea, T.C. (2006). Palifermin: a keratino-
cyte growth factor that reduces oral mucositis after stem cell
transplant for haematological malignancies. Expert Opin.
Pharmacother. 7, 2287–2299.
15. Ryu, J.K., Swann, S., LeVeque, F., et al. (2007). The impact
of concurrent granulocyte macrophage-colony stimulating
factor on radiation-induced mucositis in head and neck can-
cer patients: a double-blind placebo-controlled prospective
phase III study by Radiation Therapy Oncology Group 9901.
Int. J. Radiat. Oncol. Biol. Phys. 67, 643–650.
16. Schubert, M.M., Eduardo, F.P., Guthrie, K.A., et al. (2007).
A phase III randomized double-blind placebo-controlled
clinical trial to determine the efficacy of low level laser ther-
apy for the prevention of oral mucositis in patients under-
going hematopoietic cell transplantation. Support Care Can-
cer. 15, 1145–1154.
17. Barasch, A., Peterson, D.E., Tanzer, J.M., et al. (1995). He-
lium-neon laser effects on conditioning-induced oral mu-
cositis in bone marrow transplantation patients. Cancer. 76,
2550–2556.
18. Wong, S.F., and Wilder-Smith, P. (2002). Pilot study of laser
effects on oral mucositis in patients receiving chemotherapy.
Cancer J. 8, 247–254.
19. Bensadoun, R.J., Franquin, J.C., Ciais, G., et al. (1999). Low-
energy He/Ne laser in the prevention of radiation-induced
mucositis. A multicenter phase III randomized study in pa-
tients with head and neck cancer. Support Care Cancer. 7,
244–252.
20. Sandoval, R.L., Koga, D.H., Buloto, L.S., Suzuki, R., and Dib,
L.L. (2003). Management of chemo- and radiotherapy in-
LASER PHOTOTHERAPY FOR MUCOSITIS 143
duced oral mucositis with low-energy laser: initial results of
A.C. Camargo Hospital. J. Appl. Oral Sci. 11, 337–341.
21. Arun Maiya, G., Sagar, M.S., and Fernandes, D. (2006). Effect
of low level helium-neon (He-Ne) laser therapy in the pre-
vention and treatment of radiation induced mucositis in head
and neck cancer patients. Indian J. Med. Res. 124, 399–402.
22. Corti, L., Chiarion-Sileni, V., Aversa, S., et al. (2006). Treat-
ment of chemotherapy-induced oral mucositis with light-
emitting diode. Photomed. Laser Surg. 24, 207–213.
23. Cruz, L.B., Ribeiro, A.S., Rech, A., Rosa, L.G., Castro, C.G.
Jr., and Brunetto, A.L. (2007). Influence of low-energy laser
in the prevention of oral mucositis in children with cancer
receiving chemotherapy. Pediatr. Blood Cancer. 48, 435–440.
24. Antunes, H.S., de Azevedo, A.M., da Silva Bouzas, L.F., et
al. (2007). Low-power laser in the prevention of induced oral
mucositis in bone marrow transplantation patients: a ran-
domized trial. Blood. 109, 2250–2255.
25. Jaguar, G.C., Prado, J.D., Nishimoto, I.N., Pinheiro, M.C., de
Castro, D.O. Jr., da Cruz Perez, D.E., and Alves, F.A. (2007).
Low energy laser therapy for prevention of oral mucositis
in hematopoietic stem cell transplantation. Oral Dis. 13,
538–543.
26. Keefe, D.M., Schubert, M.M., Elting, L.S., et al. (2007). Up-
dated clinical practice guidelines for the prevention and
treatment of mucositis. Cancer. 109, 820–831.
27. World Health Organization. (1979). Handbook for reporting
results of cancer treatment. Geneva: World Health Organi-
zation, offset publication no. 48, pp. 16–17.
28. Schubert, M.M., Peterson, D.E., and Lloid, M.E. (1999). Oral
complications, in: Hematopoietic Stem Cell Transplantation.
K.G. Thomas, S.J. Forman Blume, (eds.). Malden: Blackwell
Science.
29. Filicko, J., Lazarus, H.M., and Flomenberg, N. (2003). Mu-
cosal injury in patients undergoing hematopoietic progeni-
tor cell transplantation: new approaches to prophylaxis and
treatment. Bone Marrow Transpl. 31, 1–10.
30. Scully, C., Sonis, S., and Diz, P.D. (2006). Oral mucositis. Oral
Dis. 12, 229–241.
31. Eduardo, F.P., Mehnert, D.U., Monezi, T.A., et al. (2007).
Cultured epithelial cells response to phototherapy with low
intensity laser. Lasers Surg. Med. 39, 365–372.
32. Sonis, S.T., Eilers, J.P., Epstein, J.B., et al. (1999). Validation
of a new scoring system for the assessment of clinical trial
research of oral mucositis induced by radiation or chemo-
therapy. Mucositis Study Group. Cancer. 85, 2103–2113.
33. National Cancer Institute. Common toxicity criteria doc-
ument, v.2, 1999. http://ctep.cancer.gov/reporting/ctc_
archive.html
34. Ferreira, D.M., Zangaro, R.A., Villaverde, A.B., et al. (2005).
Analgesic effect of He-Ne (632.8nm) low-level laser therapy
on acute inflammatory pain. Photomed. Laser Surg. 23,
177–181.
35. Tuner, J., and Hode, L. (2007). The Laser Therapy Handbook.
Grangesberg, Sweden: Prima Books AB.
36. Schindl, A., Merwald, H., Schindl, L., Kaun, C., and Wojta,
J. (2003). Direct stimulatory effect of low-intensity 670 nm
laser irradiation on human endothelial cell proliferation. Br.
J. Dermatol. 148, 334–336.
37. Schindl, M., Kerschan, K., Schindl, A., Schon, H., Heinzl, H.,
and Schindl, L. (1999). Induction of complete wound heal-
ing in recalcitrant ulcers by low-intensity laser irradiation
depends on ulcer cause and size. Photodermatol. Photoim-
munol. Photomed. 15, 18–21.
38. Aimbire, F., Albertini, R., Pacheco, M.T., et al. (2006). Low-
level laser therapy induces dose-dependent reduction of TN-
Falpha levels in acute inflammation. Photomed. Laser Surg.
24, 33–37.
39. Rizzi, C.F., Mauriz, J.L., Freitas Correa, D.S., et al. (2006). Ef-
fects of low-level laser therapy (LLLT) on the nuclear factor
(NF)-kappaB signaling pathway in traumatized muscle.
Lasers Surg. Med. 38, 704–713.
40. Tenovuo, J. (2002). Clinical applications of antimicrobial host
proteins lactoperoxidase, lysozyme and lactoferrin in xeros-
tomia: efficacy and safety. Oral Dis. 8, 23–29.
Address reprint requests to:
Dr. Fernanda de Paula Eduardo, D.D.S., M.S.D., Ph.D.
Rua Alves Guimarães
462 1° andar 05410-000
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E-mail: fpeduard@usp.br
EDUARDO ET AL.144
